Causes of autism: Difference between revisions

There are many known environmental, genetic, and biological causes of autism. Research indicates that genetic factors arepredominantly predominantcontribute into theits appearance. of autism; however, theThe [[heritability of autism]] is complex, and many of the genetic interactions involved are unknown.<ref name="Waye_2018" /> In rare cases, autism has been associated with [[Teratology|agents that cause birth defects]].<ref name="Arndt_2005">{{cite journal |vauthors=Arndt TL, Stodgell CJ, Rodier PM |year=2005 |title=The teratology of autism |journal=International Journal of Developmental Neuroscience |type=Review |volume=23 |issue=2–3 |pages=189–199 |doi=10.1016/j.ijdevneu.2004.11.001 |pmid=15749245 |s2cid=17797266}}</ref> Many other causes have been proposed.

Environmental factors that have been claimed to contribute to autism or exacerbate its symptoms, or that may be important to consider in future research, include certain foods,<ref name="Quan_2019">{{Cite journal | vauthors = Quan J, Panaccione N, King JA, Underwood F, Windsor JW, Coward S, Gidrewicz D, Kaplan GG | display-authors = 6 |title=A257 Association Between Celiac Disease and Autism Spectrum Disorder: A Systematic Review |date=March 2019 |journal=Journal of the Canadian Association of Gastroenterology |volume=2 |issue=Supplement_2 |pages=502–503 |doi=10.1093/jcag/gwz006.256 |issn=2515-2084 |pmc=6512700}}</ref> [[infectious disease]], [[heavy metals]], [[Solvent|solventssolvent]]s, [[diesel exhaust]], [[Polychlorinated biphenyl|PCBs]], [[phthalates]] and [[Phenol|phenolsphenol]]s used in [[plastic]] products, [[Pesticide|pesticidespesticide]]s, [[Brominatedbrominated flame retardant|brominated flame retardants]]s, [[Ethanol|alcohol]], [[smoking]], and [[Illicitillicit drug|illicit drugs]]s.<ref name="Salari_2022" /> Among these factors, vaccines have attracted much attention, as parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of [[childhood immunizations]] and an increasing likelihood of [[Measles#Public health|measles outbreaks]].<ref name="Resurgence of Measles in Europe: A">{{cite journal | vauthors = Wilder-Smith AB, Qureshi K | title = Resurgence of Measles in Europe: A Systematic Review on Parental Attitudes and Beliefs of Measles Vaccine | journal = Journal of Epidemiology and Global Health | volume = 10 | issue = 1 | pages = 46–58 | date = March 2020 | pmid = 32175710 | pmc = 7310814 | doi = 10.2991/jegh.k.191117.001 }}</ref><ref name="Beliefs around childhood vaccines i">{{cite journal | vauthors = Gidengil C, Chen C, Parker AM, Nowak S, Matthews L | title = Beliefs around childhood vaccines in the United States: A systematic review | journal = Vaccine | volume = 37 | issue = 45 | pages = 6793–6802 | date = October 2019 | pmid = 31562000 | pmc = 6949013 | doi = 10.1016/j.vaccine.2019.08.068 }}</ref> However, there is overwhelmingOverwhelming [[scientific evidence]] showing that there isshows no causal association between the [[MMR vaccine controversy|measles-mumps-rubella (MMR) vaccine and autism]]. Although there is no definitive evidence that the vaccine preservative [[Thiomersal controversy|thimerosal]] causes autism, studies have indicated a possible link between thimerosal and autism in individuals with a hereditary predisposition for autoimmune disorders.<ref name="Di_Pietrantonj_2021">{{cite journal | vauthors = Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V | title = Vaccines for measles, mumps, rubella, and varicella in children | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 11 | pages = CD004407 | date = November 2021 | pmid = 34806766 | pmc = 8607336 | doi = 10.1002/14651858.CD004407.pub5 | collaboration = Cochrane Acute Respiratory Infections Group }}</ref><ref name="Mercury as a hapten: A review of th">{{cite journal | vauthors = Kern JK, Geier DA, Mehta JA, Homme KG, Geier MR | title = Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations | journal = Journal of Trace Elements in Medicine and Biology | volume = 62 | pages = 126504 | date = December 2020 | pmid = 32534375 | doi = 10.1016/j.jtemb.2020.126504 | bibcode = 2020JTEMB..6226504K | s2cid = 219468115 }}</ref> In 2007, the [[Centers for Disease Control and Prevention|Center for Disease Control]] stated there was no support for a link between thimerosal and autism, citing evidence from several studies, as well as a continued increase in autism cases following the removal of thimerosal from childhood vaccines.<ref>{{cite web |title=Timeline: Thimerosal in Vaccines (1999-2010) |url=https://www.cdc.gov/vaccinesafety/concerns/thimerosal/timeline.html |access-date=2024-04-24 |website=CDC|date=19 August 2020 }}</ref>

Besides these early examples, the role of ''de novo'' mutations in autism first became evident when [[DNA microarray]] technologies reached sufficient resolution to allow the detection of [[copy number variation]] (CNV) in the human genome.<ref>{{cite journal |display-authors=6 |vauthors=Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Månér S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M |date=July 2004 |title=Large-scale copy number polymorphism in the human genome |journal=Science |volume=305 |issue=5683 |pages=525–528 |bibcode=2004Sci...305..525S |doi=10.1126/science.1098918 |pmid=15273396 |s2cid=20357402}}</ref><ref>{{cite journal |author-link5=Patricia K. Donahoe |display-authors=6 |vauthors=Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C |date=September 2004 |title=Detection of large-scale variation in the human genome |journal=Nature Genetics |volume=36 |issue=9 |pages=949–951 |doi=10.1038/ng1416 |pmid=15286789 |s2cid=1433674 |doi-access=free}}</ref> CNVs are the most common type of [[structural variation]] in the genome, consisting of deletions and duplications of DNA that range in size from a [[kilobase]] to a few [[Megabase|megabasesmegabase]]s. Microarray analysis has shown that ''de novo'' CNVs occur at a significantly higher rate in sporadic cases of autism as compared to the rate in their typically developing siblings and unrelated controls. A series of studies have shown that gene disrupting ''de novo'' CNVs occur approximately four times more frequently in autism than in controls and contribute to approximately 5–10% of cases.<ref name="Sebat_2007" /><ref>{{cite journal |display-authors=6 |vauthors=Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW |date=May 2014 |title=Convergence of genes and cellular pathways dysregulated in autism spectrum disorders |journal=American Journal of Human Genetics |volume=94 |issue=5 |pages=677–694 |doi=10.1016/j.ajhg.2014.03.018 |pmc=4067558 |pmid=24768552}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M |date=June 2011 |title=Rare de novo and transmitted copy-number variation in autistic spectrum disorders |journal=Neuron |volume=70 |issue=5 |pages=886–897 |doi=10.1016/j.neuron.2011.05.015 |pmid=21658582 |s2cid=11132936|doi-access=free }}</ref><ref name="Sanders_2011">{{cite journal |display-authors=6 |vauthors=Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH, Geschwind D, Roeder K, Devlin B, State MW |date=June 2011 |title=Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism |journal=Neuron |volume=70 |issue=5 |pages=863–885 |doi=10.1016/j.neuron.2011.05.002 |pmc=3939065 |pmid=21658581 |author65-link=Kathryn Roeder}}</ref> Based on these studies, there are predicted to be 130–234 autism-related CNV loci.<ref name="Sanders_2011" /> The first whole genome sequencing study to comprehensively catalog ''de novo'' [[structural variation]] at a much higher resolution than DNA microarray studies has shown that the mutation rate is approximately 20% and not elevated in autism compared to sibling controls.<ref name="Brandler_2016">{{cite journal |display-authors=6 |vauthors=Brandler WM, Antaki D, Gujral M, Noor A, Rosanio G, Chapman TR, Barrera DJ, Lin GN, Malhotra D, Watts AC, Wong LC, Estabillo JA, Gadomski TE, Hong O, Fajardo KV, Bhandari A, Owen R, Baughn M, Yuan J, Solomon T, Moyzis AG, Maile MS, Sanders SJ, Reiner GE, Vaux KK, Strom CM, Zhang K, Muotri AR, Akshoomoff N, Leal SM, Pierce K, Courchesne E, Iakoucheva LM, Corsello C, Sebat J |date=April 2016 |title=Frequency and Complexity of De Novo Structural Mutation in Autism |journal=American Journal of Human Genetics |volume=98 |issue=4 |pages=667–679 |doi=10.1016/j.ajhg.2016.02.018 |pmc=4833290 |pmid=27018473}}</ref> However, structuralStructural variants in individuals with autism are much larger and four times more likely to disrupt genes, mirroring findings from CNV studies.<ref name="Brandler_2016" />

CNV studies were closely followed by [[exome sequencing]] studies, which sequence the 1–2% of the genome that codes for proteins (the "[[exome]]"). These studies found that ''de novo'' gene inactivating mutations were observed in approximately 20% of individuals with autism, compared to 10% of unaffected siblings, suggesting the etiology of autism is driven by these mutations in around 10% of cases.<ref>{{cite journal |display-authors=6 |vauthors=Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M |date=April 2012 |title=De novo gene disruptions in children on the autistic spectrum |journal=Neuron |volume=74 |issue=2 |pages=285–299 |doi=10.1016/j.neuron.2012.04.009 |pmc=3619976 |pmid=22542183}}</ref><ref name="DeRubeis_2016">{{cite journal |display-authors=6 |vauthors=De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD |date=November 2014 |title=Synaptic, transcriptional and chromatin genes disrupted in autism |journal=Nature |volume=515 |issue=7526 |pages=209–215 |bibcode=2014Natur.515..209. |doi=10.1038/nature13772 |pmc=4402723 |pmid=25363760}}</ref><ref name="Iossifov_2014">{{cite journal |display-authors=6 |vauthors=Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M |date=November 2014 |title=The contribution of de novo coding mutations to autism spectrum disorder |journal=Nature |volume=515 |issue=7526 |pages=216–221 |bibcode=2014Natur.515..216I |doi=10.1038/nature13908 |pmc=4313871 |pmid=25363768}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ |date=April 2012 |title=Patterns and rates of exonic de novo mutations in autism spectrum disorders |journal=Nature |volume=485 |issue=7397 |pages=242–245 |bibcode=2012Natur.485..242N |doi=10.1038/nature11011 |pmc=3613847 |pmid=22495311}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW |date=April 2012 |title=De novo mutations revealed by whole-exome sequencing are strongly associated with autism |journal=Nature |volume=485 |issue=7397 |pages=237–241 |bibcode=2012Natur.485..237S |doi=10.1038/nature10945 |pmc=3667984 |pmid=22495306}}</ref><ref>{{cite journal |display-authors=6 |vauthors=O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE |date=April 2012 |title=Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |journal=Nature |volume=485 |issue=7397 |pages=246–250 |bibcode=2012Natur.485..246O |doi=10.1038/nature10989 |pmc=3350576 |pmid=22495309}}</ref> There are predicted to be 350-450 genes that significantly increase susceptibility to autism when impacted by inactivating ''de novo'' mutations.<ref>{{cite journal |vauthors=Ronemus M, Iossifov I, Levy D, Wigler M |date=February 2014 |title=The role of de novo mutations in the genetics of autism spectrum disorders |journal=Nature Reviews. Genetics |volume=15 |issue=2 |pages=133–141 |doi=10.1038/nrg3585 |pmid=24430941 |s2cid=9073763}}</ref> A further 12% of cases are predicted to be caused by protein altering [[Missensemissense mutation|missense mutations]]s that change an amino acid but do not inactivate a gene.<ref name="Iossifov_2014" /> Therefore, approximately 30% of individuals with autism have a spontaneous ''de novo'' large CNV that deletes or duplicates genes, or mutation that changes the amino acid code of an individual gene. A further 5–10% of cases have inherited [[structural variation]] at [[Locus (genetics)|loci]] known to be associated with autism, and these known structural variants may arise ''de novo'' in the parents of affected children.<ref name="Brandler_2016" />

Selected metabolicSome conditions which may (rarely) be associated with an ASD appearance are:<ref name="Hyman_2020">{{cite journal | vauthors = Hyman SL, Levy SE, Myers SM | title = Identification, Evaluation, and Management of Children With Autism Spectrum Disorder | journal = Pediatrics | volume = 145 | issue = 1 | pages = e20193447 | date = January 2020 | pmid = 31843864 | doi = 10.1542/peds.2019-3447 | s2cid = 209390456 | doi-access = free }}</ref>

===Disorders of aminoAmino acid metabolism===

===Disorders of γY-aminobutyric acid metabolism===

===Disorders of cholesterolCholesterol metabolism===

===Disorders associated with cerebralCerebral folate deficiency===

===Disorders of creatineCreatine transport or metabolism===

===Disorders of carnitineCarnitine biosynthesis===

===Disorders of purinePurine and pyrimidine metabolism===

===Lysosomal storage disorders===

===Mitochondrial disordersDNA===

* [[Mitochondrial DNA Mutationsdisease]]

===OthersBiotinidase and urea===

Most data supports a [[Polygenic disease|polygenic]], [[epistatic]] model, meaning that the disorder is caused by two or more genes and that those genes are interacting in a complex manner. Several genes, between two and fifteen in number, have been identified and could potentially contribute to disease susceptibility.<ref name="Pickles_1995">{{cite journal |vauthors=Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter M |date=September 1995 |title=Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism |journal=American Journal of Human Genetics |volume=57 |issue=3 |pages=717–726 |pmc=1801262 |pmid=7668301}}</ref><ref name="Risch_1999">{{cite journal |display-authors=6 |vauthors=Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Petersen PB, Pingree C, McMahon W, Wong DL, Cavalli-Sforza LL, Kraemer HC, Myers RM |date=August 1999 |title=A genomic screen of autism: evidence for a multilocus etiology |journal=American Journal of Human Genetics |volume=65 |issue=2 |pages=493–507 |doi=10.1086/302497 |pmc=1377948 |pmid=10417292}}</ref> However, anAn exact determination of the cause of ASD has yet to be discovered and there probably is not one single genetic cause of any particular set of disorders, leading many researchers to believe that epigenetic mechanisms, such as genomic imprinting or epimutations, may play a major role.<ref name="Samaco_2005">{{cite journal |vauthors=Samaco RC, Hogart A, LaSalle JM |date=February 2005 |title=Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3 |journal=Human Molecular Genetics |volume=14 |issue=4 |pages=483–492 |doi=10.1093/hmg/ddi045 |pmc=1224722 |pmid=15615769}}</ref><ref name="Jiang_2004">{{cite journal |display-authors=6 |vauthors=Jiang YH, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD, Liu Q, Shaffer LG, Schroer RJ, Stockton DW, Spielman RS, Stevenson RE, Beaudet AL |date=November 2004 |title=A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A |journal=American Journal of Medical Genetics. Part A |volume=131 |issue=1 |pages=1–10 |doi=10.1002/ajmg.a.30297 |pmid=15389703 |s2cid=9570482}}</ref>

[[Epigenetic]] mechanisms can contribute to disease [[Phenotype|phenotypesphenotype]]s. Epigenetic modifications include [[DNA cytosine methylation]] and post-translational modifications to [[Histone|histoneshistone]]s. These mechanisms contribute to regulating gene expression without changing the sequence of the DNA and may be influenced by exposure to environmental factors and may be heritable from parents.<ref name="Schanen_2006" /> [[Rett syndrome]] and [[Fragile X syndrome]] (FXS) are single gene disorders related to autism with overlapping symptoms that include deficient neurological development, impaired language and communication, difficulties in social interactions, and stereotyped hand gestures. It is not uncommon for a patient to be diagnosed with both autism and Rett syndrome and/or FXS. Epigenetic regulatory mechanisms play the central role in pathogenesis of these two disorders.<ref name="Samaco_2005" /><ref name="Lopez-Rangel_2006">{{cite journal |vauthors=Lopez-Rangel E, Lewis ME |date=2006 |title=Further evidence for pigenetic influence of MECP2 in Rett, autism and Angelman's syndromes |journal=Clinical Genetics |volume=69 |issue=1 |pages=23–25 |doi=10.1111/j.1399-0004.2006.00543c.x |s2cid=85160435}}</ref><ref name="Hagerman_2005">{{cite journal |vauthors=Hagerman RJ, Ono MY, Hagerman PJ |date=September 2005 |title=Recent advances in fragile X: a model for autism and neurodegeneration |journal=Current Opinion in Psychiatry |volume=18 |issue=5 |pages=490–496 |doi=10.1097/01.yco.0000179485.39520.b0 |pmid=16639106 |s2cid=33650811}}</ref>

An important basis for autism causation is also the over- or underproduction of brain permanent cells ([[Neuron|neuronsneuron]]s, [[Oligodendrocyte|oligodendrocytesoligodendrocyte]]s, and [[Astrocyte|astrocytesastrocyte]]s) by the neural precursor cells during fetal development.<ref>{{cite web |author=[[Rutgers University]] |date=August 21, 2022 |title=Scientists Discover That Irregular Production of Brain Cells Could Cause Autism |url=https://scitechdaily.com/scientists-discover-that-irregular-production-of-brain-cells-could-cause-autism/amp/ |publisher=[[SciTech (magazine)|SciTech Daily]]}}</ref>

The development of autism is associated with several [[prenatal]] risk factors, including advanced age in either parent, diabetes, bleeding, and maternal use of antibiotics and psychiatric drugs during pregnancy.<ref name="Waye_2018" /><ref>{{cite journal | vauthors = Lee E, Cho J, Kim KY | title = The Association between Autism Spectrum Disorder and Pre- and Postnatal Antibiotic Exposure in Childhood-A Systematic Review with Meta-Analysis | journal = International Journal of Environmental Research and Public Health | volume = 16 | issue = 20 | pages = 4042 | date = October 2019 | pmid = 31652518 | pmc = 6843945 | doi = 10.3390/ijerph16204042 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Morales DR, Slattery J, Evans S, Kurz X | title = Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations | journal = BMC Medicine | volume = 16 | issue = 1 | pages = 6 | date = January 2018 | pmid = 29332605 | pmc = 5767968 | doi = 10.1186/s12916-017-0993-3 | doi-access = free }}</ref> Autism has been linked to birth defect agents acting during the first eight weeks from [[Human fertilization|conception]], though these cases are rare.<ref>{{cite journal | vauthors = Roullet FI, Lai JK, Foster JA | title = In utero exposure to valproic acid and autism--a current review of clinical and animal studies | journal = Neurotoxicology and Teratology | volume = 36 | issue = | pages = 47–56 | year = 2013 | pmid = 23395807 | doi = 10.1016/j.ntt.2013.01.004 | bibcode = 2013NTxT...36...47R | type = Review }}</ref> If the mother of the child is dealing with autoimmune conditions or disorders while pregnant, it may have an effect on the child's development of autism.<ref name="Han_2021">{{cite journal | vauthors = Han VX, Patel S, Jones HF, Nielsen TC, Mohammad SS, Hofer MJ, Gold W, Brilot F, Lain SJ, Nassar N, Dale RC | display-authors = 6 | title = Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review | journal = Translational Psychiatry | volume = 11 | issue = 1 | pages = 71 | date = January 2021 | pmid = 33479207 | pmc = 7820474 | doi = 10.1038/s41398-021-01198-w }}</ref> All of these factors can cause inflammation or impair immune signaling in one way or another.<ref name="Han_2021" />

[[Sleep apnea]] can result in intermittent [[Hypoxia (medical)|hypoxia]] and has been increasing in prevalence due in part to the [[obesity]] epidemic. The known maternal risk factors for autism diagnosis in her offspring are similar to the risk factors for sleep apnea. For example, advanced maternal age, maternal [[obesity]], maternal [[type 2 diabetes]] and maternal [[hypertension]] all increase the risk of autism in her offspring.<ref name="Maternal diabetes and the risk of a">{{cite journal |vauthors=Xu G, Jing J, Bowers K, Liu B, Bao W |date=April 2014 |title=Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis |journal=Journal of Autism and Developmental Disorders |volume=44 |issue=4 |pages=766–775 |doi=10.1007/s10803-013-1928-2 |pmc=4181720 |pmid=24057131}}</ref><ref>{{cite journal |vauthors=Maher GM, O'Keeffe GW, Kearney PM, Kenny LC, Dinan TG, Mattsson M, Khashan AS |date=August 2018 |title=Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis |journal=JAMA Psychiatry |volume=75 |issue=8 |pages=809–819 |doi=10.1001/jamapsychiatry.2018.0854 |pmc=6143097 |pmid=29874359}}</ref><ref>{{cite journal |vauthors=Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A |date=May 2012 |title=Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=51 |issue=5 |pages=477–486.e1 |doi=10.1016/j.jaac.2012.02.018 |pmid=22525954}}</ref><ref>{{cite journal |vauthors=Wang Y, Tang S, Xu S, Weng S, Liu Z |date=September 2016 |title=Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis |journal=Scientific Reports |volume=6 |pages=34248 |bibcode=2016NatSR...634248W |doi=10.1038/srep34248 |pmc=5043237 |pmid=27687989}}</ref> Likewise, these are all known risk factors for sleep apnea.<ref>{{cite journal |display-authors=6 |vauthors=Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD, Pickering TG |date=April 2000 |title=Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study |journal=JAMA |volume=283 |issue=14 |pages=1829–1836 |doi=10.1001/jama.283.14.1829 |pmid=10770144}}</ref><ref>{{cite journal |vauthors=Muraki I, Wada H, Tanigawa T |date=September 2018 |title=Sleep apnea and type 2 diabetes |journal=Journal of Diabetes Investigation |volume=9 |issue=5 |pages=991–997 |doi=10.1111/jdi.12823 |pmc=6123041 |pmid=29453905 |s2cid=4871197}}</ref><ref>{{cite journal |vauthors=Punjabi NM |date=February 2008 |title=The epidemiology of adult obstructive sleep apnea |journal=Proceedings of the American Thoracic Society |volume=5 |issue=2 |pages=136–143 |doi=10.1513/pats.200709-155MG |pmc=2645248 |pmid=18250205}}</ref>

One study found that gestational sleep apnea was associated with low reading test scores in children and that this effect may be mediated by an increased risk of the child having sleep apnea themselves.<ref>{{cite journal | vauthors = Bin YS, Cistulli PA, Roberts CL, Ford JB | title = Childhood Health and Educational Outcomes Associated With Maternal Sleep Apnea: A Population Record-Linkage Study | journal = Sleep | volume = 40 | issue = 11 | date = November 2017 | pmid = 29029347 | doi = 10.1093/sleep/zsx158 | doi-access = free }}</ref> Another study reported low social development scores in 64% of infants born to mothers with sleep apnea compared to 25% of infants born to controls, suggesting sleep apnea in pregnancy may have an effect on offspring neurodevelopment.<ref name="Tauman_2015">{{cite journal | vauthors = Tauman R, Zuk L, Uliel-Sibony S, Ascher-Landsberg J, Katsav S, Farber M, Sivan Y, Bassan H | display-authors = 6 | title = The effect of maternal sleep-disordered breathing on the infant's neurodevelopment | journal = American Journal of Obstetrics and Gynecology | volume = 212 | issue = 5 | pages = 656.e1–656.e7 | date = May 2015 | pmid = 25576821 | doi = 10.1016/j.ajog.2015.01.001 }}</ref> There was also an increase in the amount of snoring the mothers with sleep apnea reported in their infants when compared to controls.<ref name="Tauman_2015" /> Children with sleep apnea have "hyperactivity, attention problems, aggressivity, lower social competency, poorer communication, and/or diminished adaptive skills".<ref name="pmid235439012">{{cite journal | vauthors = Perfect MM, Archbold K, Goodwin JL, Levine-Donnerstein D, Quan SF | title = Risk of behavioral and adaptive functioning difficulties in youth with previous and current sleep disordered breathing | journal = Sleep | volume = 36 | issue = 4 | pages = 517–525B | date = April 2013 | pmid = 23543901 | pmc = 3595180 | doi = 10.5665/sleep.2536 }}</ref> One study found significant improvements in ADHD-like symptoms, aggression, social problems and thought problems in autistic children who underwent [[Tonsillectomy|adenotonsillectomy]] for sleep apnea.<ref>{{cite journal | vauthors = Murata E, Mohri I, Kato-Nishimura K, Iimura J, Ogawa M, Tachibana M, Ohno Y, Taniike M | display-authors = 6 | title = Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder | journal = Research in Developmental Disabilities | volume = 65 | pages = 127–139 | date = June 2017 | pmid = 28514706 | doi = 10.1016/j.ridd.2017.04.012 | doi-access = free }}</ref> Sleep problems in autism have been linked in a study to brain changes, particularly in the hippocampus, though this study does not prove causation.<ref>{{cite journal | vauthors = MacDuffie KE, Shen MD, Dager SR, Styner MA, Kim SH, Paterson S, Pandey J, St John T, Elison JT, Wolff JJ, Swanson MR, Botteron KN, Zwaigenbaum L, Piven J, Estes AM | display-authors = 6 | title = Sleep Onset Problems and Subcortical Development in Infants Later Diagnosed With Autism Spectrum Disorder | journal = The American Journal of Psychiatry | volume = 177 | issue = 6 | pages = 518–525 | date = June 2020 | pmid = 32375538 | pmc = 7519575 | doi = 10.1176/appi.ajp.2019.19060666 }}</ref> A common presentation of sleep apnea in children with autism is insomnia.<ref>{{Cite journal |lastlast1=Santapuram |firstfirst1=Pooja |last2=Chen |first2=Heidi |last3=Weitlauf |first3=Amy S. |last4=Ghani |first4=Muhammad Owais A. |last5=Whigham |first5=Amy S. |date=July 2022-07 |title=Investigating differences in symptomatology and age at diagnosis of obstructive sleep apnea in children with and without autism |url=https://pubmed.ncbi.nlm.nih.gov/35636082/#:~:text=Children%20with%20OSA%20can%20present,in%20children%20with%20both%20conditions. |journal=International Journal of Pediatric Otorhinolaryngology |volume=158 |pages=111191 |doi=10.1016/j.ijporl.2022.111191 |issn=1872-8464 |pmid=35636082}}</ref> All known genetic syndromes which are linked to autism have a high prevalence of sleep apnea. The prevalence of sleep apnea in Down's Syndrome is 50% - 100%.<ref>{{Cite journal |lastlast1=Maris |firstfirst1=Mieke |last2=Verhulst |first2=Stijn |last3=Wojciechowski |first3=Marek |last4=Van de Heyning |first4=Paul |last5=Boudewyns |first5=An |date=2016-03-01 |title=Prevalence of Obstructive Sleep Apnea in Children with Down Syndrome |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763351/ |journal=Sleep |volume=39 |issue=3 |pages=699–704 |doi=10.5665/sleep.5554 |issn=0161-8105 |pmc=4763351 |pmid=26612391}}</ref>. Sleep problems and OSA in this population have been linked to language development.<ref>{{Cite journal |lastlast1=Lee |firstfirst1=Ni-Chung |last2=Hsu |first2=Wei-Chung |last3=Chang |first3=Lih-Maan |last4=Chen |first4=Yi-Chen |last5=Huang |first5=Po-Tsang |last6=Chien |first6=Chun-Chin |last7=Chien |first7=Yin-Hsiu |last8=Chen |first8=Chi-Ling |last9=Hwu |first9=Wuh-Liang |last10=Lee |first10=Pei-Lin |date=January 2020-01 |title=REM sleep and sleep apnea are associated with language function in Down syndrome children: An analysis of a community sample |url=https://pubmed.ncbi.nlm.nih.gov/31378642/ |journal=Journal of the Formosan Medical Association = Taiwan Yi Zhi |volume=119 |issue=1 Pt 3 |pages=516–523 |doi=10.1016/j.jfma.2019.07.015 |issn=0929-6646 |pmid=31378642|doi-access=free }}</ref> Since autism manifests in the early developmental period, sleep apnea in Down's Syndrome and other genetic syndromes such as Fragile X start early (at infancy or shortly after), and sleep disturbances alter brain development,<ref>{{Cite journal |last1=Lord |first1=Julia S. |last2=Gay |first2=Sean M. |last3=Harper |first3=Kathryn M. |last4=Nikolova |first4=Viktoriya D. |last5=Smith |first5=Kirsten M. |last6=Moy |first6=Sheryl S. |last7=Diering |first7=Graham H. |date=2022-08-29 |title=Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice |journal=Molecular Autism |volume=13 |issue=1 |pages=35 |doi=10.1186/s13229-022-00514-5 |doi-access=free |issn=2040-2392 |pmc=9425965 |pmid=36038911}}</ref> it's plausible that some of the neurodevelopmental differences seen in these genetic syndromes are at least partially caused by the effects of untreated sleep apnea.

=== Infectious processeshypotheses ===

PrenatalOne hypothesis suggests that prenatal viral infection hasmay beencontribute calledto the principal non-genetic causedevelopment of autism. Prenatal exposure to [[rubella]] or [[cytomegalovirus]] activates the mother's [[immune response]] and may greatly increase the risk for autism in mice.<ref name="Libbey_2005">{{cite journal | vauthors = Libbey JE, Sweeten TL, McMahon WM, Fujinami RS | title = Autistic disorder and viral infections | journal = Journal of Neurovirology | volume = 11 | issue = 1 | pages = 1–10 | date = February 2005 | pmid = 15804954 | doi = 10.1080/13550280590900553 | type = Review | s2cid = 9962647 }}</ref> [[Congenital rubella syndrome]] is the most convincing environmental cause of autism.<ref>{{cite journal | vauthors = Mendelsohn NJ, Schaefer GB | title = Genetic evaluation of autism | journal = Seminars in Pediatric Neurology | volume = 15 | issue = 1 | pages = 27–31 | date = March 2008 | pmid = 18342258 | doi = 10.1016/j.spen.2008.01.005 | type = Review }}</ref> Infection-associated immunological events in early pregnancy may affect neural development more than infections in late pregnancy, not only for autism, but also for psychiatric disorders of presumed neurodevelopmental origin, notably [[schizophrenia]].<ref>{{cite journal | vauthors = Meyer U, Yee BK, Feldon J | title = The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? | journal = The Neuroscientist | volume = 13 | issue = 3 | pages = 241–256 | date = June 2007 | pmid = 17519367 | doi = 10.1177/1073858406296401 | type = Review | s2cid = 26096561 }}</ref>

[[Teratogen|Teratogens]]s are environmental agents that cause [[Birthbirth defect|birth defects]]s. Some agents that are theorized to cause birth defects have also been suggested as potential autism risk factors, although there is little to no scientific evidence to back such claims. These include exposure of the embryo to [[valproic acid]],<ref name="Waye_2018" /> [[paracetamol]],<ref>{{cite journal | vauthors = Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, García-Esteban R, Galán IR, Tardón A, Rodríguez-Bernal CL, Iñiguez C, Andiarena A, Santa-Marina L, Sunyer J | display-authors = 6 | title = Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms | journal = International Journal of Epidemiology | volume = 45 | issue = 6 | pages = 1987–1996 | date = December 2016 | pmid = 27353198 | doi = 10.1093/ije/dyw115 | doi-access = free }}</ref> [[thalidomide]] or [[misoprostol]].<ref name="Dufour_2011">{{cite journal | vauthors = Dufour-Rainfray D, Vourc'h P, Tourlet S, Guilloteau D, Chalon S, Andres CR | title = Fetal exposure to teratogens: evidence of genes involved in autism | journal = Neuroscience and Biobehavioral Reviews | volume = 35 | issue = 5 | pages = 1254–1265 | date = April 2011 | pmid = 21195109 | doi = 10.1016/j.neubiorev.2010.12.013 | type = Review | s2cid = 5180756 }}</ref> These cases are rare.<ref>{{cite journal | vauthors = Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C | title = Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review | journal = International Journal of Developmental Neuroscience | volume = 23 | issue = 2–3 | pages = 201–219 | year = 2005 | pmid = 15749246 | doi = 10.1016/j.ijdevneu.2004.06.007 |s2cid=14248227}}</ref> Questions have also been raised whether [[ethanol]] (grain alcohol) increases autism risk, as part of [[fetal alcohol syndrome]] or alcohol-related birth defects.<ref name="Dufour_2011" /> All known teratogens appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, it is strong evidence that autism arises very early in development.<ref name="Arndt_2005" />

A small but significant link has beenwas shown to exist between prenatal exposure to airborne pollutants and autism risk. However, thisThis finding was not consistent across studies, and exposure to pollutants was measured indirectly.<ref>{{cite journal | vauthors = Modabbernia A, Velthorst E, Reichenberg A | title = Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses | journal = Molecular Autism | volume = 8 | issue = 1 | pages = 13 |date=2017-03-17 | pmid = 28331572 | pmc = 5356236 | doi = 10.1186/s13229-017-0121-4 | doi-access = free }}</ref>

[[Thyroid]] problems that lead to [[thyroxine]] deficiency in the mother in weeks 8–12 of pregnancy have been postulated to produce changes in the fetal brain leading to autism. Thyroxine deficiencies can be caused by inadequate [[iodine]] in the diet, and by environmental agents that [[Goitrogen|interfere with iodine uptake]] or [[Antithyroid agent|act against thyroid hormones]]. Possible environmental agents include [[Flavonoid|flavonoidsflavonoid]]s in food, [[tobacco smoke]], and most [[Herbicide|herbicidesherbicide]]s. This hypothesis has not been tested.<ref>{{cite journal |vauthors=Román GC |date=November 2007 |title=Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents |journal=Journal of the Neurological Sciences |type=Review |volume=262 |issue=1–2 |pages=15–26 |doi=10.1016/j.jns.2007.06.023 |pmid=17651757 |s2cid=31805494}}</ref>

Diabetes in the mother during pregnancy is a significant risk factor for autism; a 2009 meta-analysis found that [[gestational diabetes]] was associated with a twofold increased risk. A 2014 review also found that maternal diabetes was significantly associated with an increased risk of autism.<ref>{{cite journal |vauthors=Xu G, Jing J, Bowers K, Liu B, Bao W |date=April 2014 |titlename="Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis |journal=Journal of Autism and Developmental Disorders |volume=44 |issue=4 |pages=766–775 |doi=10.1007/s10803-013-1928-2 |pmc=4181720 |pmid=24057131}}<"/ref> Although diabetes causes metabolic and hormonal abnormalities and [[oxidative stress]], no biological mechanism is known for the association between gestational diabetes and autism risk.<ref name="Gardener_2009">{{cite journal |vauthors=Gardener H, Spiegelman D, Buka SL |date=July 2009 |title=Prenatal risk factors for autism: comprehensive meta-analysis |journal=The British Journal of Psychiatry |type=Review, meta-analysis |volume=195 |issue=1 |pages=7–14 |doi=10.1192/bjp.bp.108.051672 |pmc=3712619 |pmid=19567888}}</ref>

[[Prenatal stress]], consisting of exposure to life events or environmental factors that distress an expectant mother, has been hypothesized to contribute to autism, possibly as part of a gene-environment interaction. Autism has been reported to be associated with prenatal stress both with retrospective studies that examined stressors such as job loss and family discord, and with natural experiments involving prenatal exposure to storms; animal studies have reported that prenatal stress can disrupt brain development and produce behaviors resembling symptoms of autism.<ref>{{cite journal | vauthors = Kinney DK, Munir KM, Crowley DJ, Miller AM | title = Prenatal stress and risk for autism | journal = Neuroscience and Biobehavioral Reviews | volume = 32 | issue = 8 | pages = 1519–1532 | date = October 2008 | pmid = 18598714 | pmc = 2632594 | doi = 10.1016/j.neubiorev.2008.06.004 | type = Review }}</ref> However, otherOther studies have cast doubtsdoubt on this association, notably population based studies in England and Sweden finding no link between stressful life events and autism.<ref>{{cite journal | vauthors = Rai D, Golding J, Magnusson C, Steer C, Lewis G, Dalman C | title = Prenatal and early life exposure to stressful life events and risk of autism spectrum disorders: population-based studies in Sweden and England | journal = PLOS ONE | volume = 7 | issue = 6 | pages = e38893 | year = 2012 | pmid = 22719977 | pmc = 3374800 | doi = 10.1371/journal.pone.0038893 | doi-access = free | bibcode = 2012PLoSO...738893R }}</ref>

Autism is associated with some [[perinatal]] and [[obstetric]] conditions. Infants that are born pre-term often have various neurodevelopmental impairments related to motor skills, cognition, receptive and expressive language, and socio-emotional capabilities.<ref name="Rogers_2018">{{cite journal | vauthors = Rogers CE, Lean RE, Wheelock MD, Smyser CD | title = Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children | journal = Journal of Neurodevelopmental Disorders | volume = 10 | issue = 1 | pages = 38 | date = December 2018 | pmid = 30541449 | pmc = 6291944 | doi = 10.1186/s11689-018-9253-x | eissn = 1866-1955 | doi-access = free }}</ref> Pre-term infants are also at a higher risk of having various neurodevelopmental disorders such as cerebral palsy and autism, as well as psychiatric disorders related to attention, anxiety, and impaired social communication.<ref name="Rogers_2018" /> It has also been proposed that the functions of the hypothalamic-pituitary-adrenal axis and brain connectivity in pre-term infants may be affected by NICU-related stress resulting in deficits in emotional regulation and socio-emotional capabilities.<ref name="Rogers_2018" /> A 2019 analysis of perinatal and neonatal [[risk factors]] found that autism was associated with abnormal fetal positioning, umbilical cord complications, low [[Apgar score|5-minute Apgar]] score, low birth weight and gestation duration, fetal distress, [[meconium aspiration syndrome]], trauma or injury during birth, maternal hemorrhaging, multiple birth, feeding disorders, neonatal anemia, birth defects/malformation, incompatibility with maternal blood type, and [[Hyperbilirubinemia|jaundice/hyperbilirubinemia.]] These associations do not denote a causal relationship for any individual factor.<ref>{{cite journal | vauthors = Gardener H, Spiegelman D, Buka SL | title = Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis | journal = Pediatrics | volume = 128 | issue = 2 | pages = 344–355 | date = August 2011 | pmid = 21746727 | pmc = 3387855 | doi = 10.1542/peds.2010-1036 }}</ref> There is growing evidence that perinatal exposure to [[air pollution]] may be a risk factor for autism, although this evidence has methodological limitations, including a small number of studies and failure to control for potential confounding factors.<ref>{{cite journal | vauthors = Weisskopf MG, Kioumourtzoglou MA, Roberts AL | title = Air Pollution and Autism Spectrum Disorders: Causal or Confounded? | journal = Current Environmental Health Reports | volume = 2 | issue = 4 | pages = 430–439 | date = December 2015 | pmid = 26399256 | pmc = 4737505 | doi = 10.1007/s40572-015-0073-9 | bibcode = 2015CEHR....2..430W }}</ref><ref>{{cite journal | vauthors = Flores-Pajot MC, Ofner M, Do MT, Lavigne E, Villeneuve PJ | title = Childhood autism spectrum disorders and exposure to nitrogen dioxide, and particulate matter air pollution: A review and meta-analysis | journal = Environmental Research | volume = 151 | issue = | pages = 763–776 | date = November 2016 | pmid = 27609410 | pmc = | doi = 10.1016/j.envres.2016.07.030 | bibcode = 2016ER....151..763F }}</ref> A few studies have found an association between autism and frequent use of acetaminophen (e.g. Tylenol, Paracetamol) by the mother during pregnancy.<ref>{{cite journal | vauthors = Parker W, Hornik CD, Bilbo S, Holzknecht ZE, Gentry L, Rao R, Lin SS, Herbert MR, Nevison CD | display-authors = 6 | title = The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism | journal = The Journal of International Medical Research | volume = 45 | issue = 2 | pages = 407–438 | date = April 2017 | pmid = 28415925 | pmc = 5536672 | doi = 10.1177/0300060517693423 }}</ref><ref>{{cite journal | vauthors = Borchers A, Pieler T | title = Programming pluripotent precursor cells derived from Xenopus embryos to generate specific tissues and organs | journal = Genes | volume = 1 | issue = 3 | pages = 413–426 | date = November 2010 | pmid = 24710095 | doi = 10.3390/e14112227 | pmc = 3966229 | bibcode = 2012Entrp..14.2227S | doi-access = free }}</ref> This association does not necessarily demonstrate a causal relationship.

This theory hypothesizes that autoantibodies that target the brain or elements of brain metabolism may cause or exacerbate autism. It is related to the [[#Maternal infection|maternal infection]]{{Broken anchor|date=2024-03-24|bot=User:Cewbot/log/20201008/configuration|reason= The anchor (Maternal infection) [[Special:Diff/413694597|has been deleted]].}} theory, except that it postulates that the effect is caused by the individual's own antibodies, possibly due to an environmental trigger after birth. It is also related to several other hypothesized causes; for example, [[#Viral infection|viral infection]] has been hypothesized to cause autism via an autoimmune mechanism.<ref>{{cite journal | vauthors = Ashwood P, Van de Water J | title = Is autism an autoimmune disease? | journal = Autoimmunity Reviews | volume = 3 | issue = 7–8 | pages = 557–562 | date = November 2004 | pmid = 15546805 | doi = 10.1016/j.autrev.2004.07.036 | type = Review }}</ref>

The "[[leaky gut syndrome]]" hypothesis developed by [[Andrew Wakefield]], known for [[MMR vaccine and autism|his fraudulent study on another cause of autism]], is popular among parents of children with autism.<ref>{{cite journal | title = Retraction--Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children | journal = Lancet | volume = 375 | issue = 9713 | pages = 445 | date = February 2010 | pmid = 20137807 | doi = 10.1016/s0140-6736(10)60175-4 | s2cid = 26364726 | vauthors = ((The Editors of The Lancet)) }}</ref><ref>{{cite journal | vauthors = Bezawada N, Phang TH, Hold GL, Hansen R | title = Autism Spectrum Disorder and the Gut Microbiota in Children: A Systematic Review | journal = Annals of Nutrition & Metabolism | volume = 76 | issue = 1 | pages = 16–29 | date = 2020 | pmid = 31982866 | doi = 10.1159/000505363 | s2cid = 210922352 | eissn = 1421-9697 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Almeida C, Oliveira R, Soares R, Barata P | title = Influence of gut microbiota dysbiosis on brain function: a systematic review | journal = Porto Biomedical Journal | volume = 5 | issue = 2 | page = 1 | date = 2020 | pmid = 33299942 | pmc = 7722401 | doi = 10.1097/j.pbj.0000000000000059 | eissn = 2444-8672 }}</ref> It is based on the idea that defects in the [[Intestinal mucosal barrier|intestinal barrier]] produce an excessive increase in [[intestinal permeability]], allowing substances present in the intestine (including bacteria, environmental toxins, and food [[Antigen|antigensantigen]]s) to pass into the blood. The data supporting this theory are limited and contradictory, since both increased intestinal permeability and normal permeability have been documented in people with autism. Studies with mice provide some support to this theory and suggest the importance of [[intestinal flora]], demonstrating that the normalization of the intestinal barrier was associated with an improvement in some of the autism-like behaviors.<ref name="Rao_2016" /> Studies on subgroups of people with autism showed the presence of high plasma levels of [[zonulin]], a protein that regulates permeability opening the "pores" of the intestinal wall, as well as intestinal [[dysbiosis]] (reduced levels of ''[[Bifidobacteria]]'' and increased abundance of ''[[Akkermansia muciniphila]]'', ''[[Escherichia coli]]'', ''[[Clostridia]]'' and [[Candida (fungus)|''Candida'' fungi]] that promote the production of [[Proinflammatoryproinflammatory cytokine|proinflammatory cytokines]]s, all of which produces excessive intestinal permeability.<ref name="Azhari_2019">{{cite journal | vauthors = Azhari A, Azizan F, Esposito G | title = A systematic review of gut-immune-brain mechanisms in Autism Spectrum Disorder | journal = Developmental Psychobiology | volume = 61 | issue = 5 | pages = 752–771 | date = July 2019 | pmid = 30523646 | doi = 10.1002/dev.21803 | type = Systematic Review | s2cid = 54523742 | hdl = 10220/49107 | hdl-access = free }}</ref> This allows passage of bacterial [[Lipopolysaccharide|endotoxins]] from the gut into the bloodstream, stimulating liver cells to secrete [[tumor necrosis factor alpha]] (TNFα), which modulates [[blood–brain barrier]] permeability. Studies on ASD people showed that TNFα cascades produce proinflammatory cytokines, leading to peripheral inflammation and activation of microglia in the brain, which indicates [[neuroinflammation]].<ref name="Azhari_2019" /> In addition, neuroactive [[Opioidopioid peptide|opioid peptides]]s from digested foods have been shown to leak into the bloodstream and permeate the blood–brain barrier, influencing neural cells and causing autistic symptoms.<ref name="Azhari_2019" /> (See [[#Endogenous opiate precursor theory|Endogenous opiate precursor theory]])

=== Nutrition-related Factorsfactors ===

=== Toxic Exposureexposure ===

Multiple studies have made attemptsattempted to study the relationship between toxic exposure and autism. However, these studies often met withdespite limitations related to the measurement of toxic exposure the methods for which were often indirect and cross-sectional. Systematic reviews have been conducted for numerous toxins including air pollution, thimerosal, inorganic mercury, and levels of heavy metals in hair, nails, and bodily fluids.<ref name="Modabbernia_2017" />

Although no link was found to exist between the vaccine additive thiomersal and autism risk, this association may hold true for individuals with a hereditary predisposition for autoimmune disorders.<ref>{{cite journal | vauthors name= Kern JK, Geier DA, Mehta JA, Homme KG, Geier MR | title = "Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations | journal = Journal of Trace Elements in Medicine and Biology | volume = 62 | pages = 126504 | date = December 2020 | pmid = 32534375 | doi = 10.1016/j.jtemb.2020.126504 | s2cid = 219468115 }}<th"/ref><ref name="Modabbernia_2017" />

Environmental exposure to inorganic mercury may be associated with higher autism risk, with high levels of mercury in the body being a valid [[Pathogenic theories of disease|disease-causing agent]] for autism.<ref name="Modabbernia_2017" /><ref name="Jafari_Mohammadabadi_2020">{{cite journal | vauthors = Jafari Mohammadabadi H, Rahmatian A, Sayehmiri F, Rafiei M | title = The Relationship Between the Level of Copper, Lead, Mercury and Autism Disorders: A Meta-Analysis | language = English | journal = Pediatric Health, Medicine and Therapeutics | volume = 11 | pages = 369–378 | date = 2020-09-21 | pmid = 33061742 | pmc = 7519826 | doi = 10.2147/PHMT.S210042 | doi-access = free }}</ref>

Significant evidence has not been found of an association between autism and the concentration of mercury, copper, cadmium, selenium, and chromium in the hair, nails, and bodily fluids.<ref name="Modabbernia_2017" /><ref>{{cite journal | vauthors = Islam GM, Rahman MM, Hasan MI, Tadesse AW, Hamadani JD, Hamer DH | title = Hair, serum and urine chromium levels in children with cognitive defects: A systematic review and meta-analysis of case control studies | journal = Chemosphere | volume = 291 | issue = Pt 2 | pages = 133017 | date = March 2022 | pmid = 34813844 | pmc = 8792285 | doi = 10.1016/j.chemosphere.2021.133017 | bibcode = 2022Chmsp.291m3017I29133017I | eissn = 1879-1298 }}</ref><ref name="Jafari_Mohammadabadi_2020" /> Levels of lead were found to be significantly higher in individuals with autism.<ref name="Modabbernia_2017" /><ref name="Jafari_Mohammadabadi_2020" /> The precision and consistency of results were not maintained across studies and were influenced by an outlier study.<ref name="Modabbernia_2017" /> The atypical eating behaviors of autistic children, along with habitual mouthing and [[Pica (disorder)|pica]], make it hard to determine whether increased lead levels are a cause or a consequence of autism.<ref name="Zafeiriou_2006">{{cite journal | vauthors = Zafeiriou DI, Ververi A, Vargiami E | title = Childhood autism and associated comorbidities | journal = Brain & Development | volume = 29 | issue = 5 | pages = 257–272 | date = June 2007 | pmid = 17084999 | doi = 10.1016/j.braindev.2006.09.003 | type = Review | s2cid = 16386209 }}</ref>

[[Oxidative stress]], oxidative [[DNA damage (naturally occurring)|DNA damage]] and disruptions of [[DNA]] repair have been postulated to play a role in the etiopathology of both ASD and schizophrenia.<ref name="pmid272582602">{{cite journal | vauthors = Markkanen E, Meyer U, Dianov GL | title = DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond | journal = International Journal of Molecular Sciences | volume = 17 | issue = 6 | page = 856 | date = June 2016 | pmid = 27258260 | pmc = 4926390 | doi = 10.3390/ijms17060856 | doi-access = free }}</ref> Physiological factors and mechanisms influence by oxidative stress are believed to be highly influential to autism risk. Interactions between environmental and genetic factors may increase oxidative stress in children with autism.<ref name="Bjørklund_2020">{{cite journal | vauthors = Bjørklund G, Meguid NA, El-Bana MA, Tinkov AA, Saad K, Dadar M, Hemimi M, Skalny AV, Hosnedlová B, Kizek R, Osredkar J, Urbina MA, Fabjan T, El-Houfey AA, Kałużna-Czaplińska J, Gątarek P, Chirumbolo S | display-authors = 6 | title = Oxidative Stress in Autism Spectrum Disorder | journal = Molecular Neurobiology | volume = 57 | issue = 5 | pages = 2314–2332 | date = May 2020 | pmid = 32026227 | doi = 10.1007/s12035-019-01742-2 | s2cid = 255484540 }}</ref> This theory hypothesizes that toxicity and [[oxidative stress]] may cause autism in some cases. Evidence includes genetic effects on metabolic pathways, reduced antioxidant capacity, enzyme changes, and enhanced biomarkers for oxidative stress.<ref name="Bjørklund_2020" /> One theory is that stress damages [[Purkinje cell|Purkinje cells]]s in the [[cerebellum]] after birth, and it is possible that [[glutathione]] is involved.<ref>{{cite journal | vauthors = Kern JK, Jones AM | title = Evidence of toxicity, oxidative stress, and neuronal insult in autism | journal = Journal of Toxicology and Environmental Health Part B: Critical Reviews | volume = 9 | issue = 6 | pages = 485–499 | year = 2006 | pmid = 17090484 | doi = 10.1080/10937400600882079 | bibcode = 2006JTEHB...9..485K | type = Review | s2cid = 1096750 }}</ref> Polymorphism of genes involved metabolization of glutathione is evidenced by lower levels of total glutathione, and higher levels of oxidized glutathione in autistic children.<ref name="Bjørklund_2020" /><ref>{{cite journal | vauthors = Ghanizadeh A, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A | title = Glutathione-related factors and oxidative stress in autism, a review | journal = Current Medicinal Chemistry | volume = 19 | issue = 23 | pages = 4000–4005 | year = 2012 | pmid = 22708999 | doi = 10.2174/092986712802002572 | type = Review }}</ref> Based on this theory, [[Antioxidant|antioxidantsantioxidant]]s may be a useful treatment for autism.<ref>{{cite journal | vauthors = Villagonzalo KA, Dodd S, Dean O, Gray K, Tonge B, Berk M | title = Oxidative pathways as a drug target for the treatment of autism | journal = Expert Opinion on Therapeutic Targets | volume = 14 | issue = 12 | pages = 1301–1310 | date = December 2010 | pmid = 20954799 | doi = 10.1517/14728222.2010.528394 | type = Review | s2cid = 44864562 }}</ref> Environmental factors can influence oxidative stress pre, peri, and postnatally and include heavy metals, infection, certain drugs, and toxic exposure from various sources including cigarette smoke, air pollutants, and organophosphate pesticides.<ref name="Bjørklund_2020" />

Beyond the genetic, epigenetic, and biological factors that can contribute to an autism diagnosis are theories related to the "autistic identity.".<ref name="Moore_2022">{{Cite journal | vauthors = Moore I, Morgan G, Welham A, Russell G |date=November 2022 |title=The intersection of autism and gender in the negotiation of identity: A systematic review and metasynthesis |journal=Feminism & Psychology |language=en |volume=32 |issue=4 |pages=421–442 |doi=10.1177/09593535221074806 |s2cid=246893906 |issn=0959-3535|doi-access=free }}</ref> It has been theorized that perceptions towards the characteristics of autistic individuals have been heavily influenced by neurotypical ideologies and social norms.<ref name="Moore_2022" />

One theory on the evolutionary and biological origins of autism traits in ''[[Homo sapiens]]'' that has gained recent attention in the 2010s and 2020s is that some genes linked to autism may have originated from early humans crossbreeding with [[Neanderthal]]s, an extinct group of [[archaic humans]] (generally regarded as a distinct species, ''Homo neanderthalensis'', though some regard it as a subspecies of ''Homo sapiens'', referred to as ''H. sapiens neanderthalensis'') who lived in [[Eurasia]] until about 40,000 years ago.

The first Neanderthal genome sequence was published in 2010, and strongly indicated interbreeding between Neanderthals and early modern humans.<ref name=green>{{cite journal |last1=Green |first1=R. E. |last2=Krause |first2=J. |last3=Briggs |first3=A. W. |display-authors=3 |last4=Maricic |first4=T. |last5=Stenzel |first5=U. |last6=Kircher |first6=M. |last7=Patterson |first7=N. |last8=Li |first8=H. |last9=Zhai |first9=W. |last10=Fritz |first10=M. H. Y. |last11=Hansen |first11=N. F. |last12=Durand |first12=E. Y. |last13=Malaspinas |first13=A. S. |last14=Jensen |first14=J. D. |last15=Marques-Bonet |first15=T. |last16=Alkan |first16=C. |last17=Prüfer |first17=K. |last18=Meyer |first18=M. |last19=Burbano |first19=H. A. |last20=Good |first20=J. 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D. |last7=Comas |first7=D. |last8=Lalueza-Fox |first8=C. |last9=Caramelli |first9=D.|title=North African populations carry the signature of admixture with Neandertals |journal=PLOS ONE |year= 2012 |volume=7 |issue=10 |pages=e47765 |doi=10.1371/journal.pone.0047765 |pmid=23082212 |pmc=3474783 |bibcode=2012PLoSO...747765S|doi-access=free }}</ref> The genomes of all studied modern populations contain Neanderthal DNA.<ref name=green/><ref name=sankararaman2014>{{cite journal |last1=Sankararaman |first1=S.|last2=Mallick |first2=S. |last3=Dannemann |first3=M. |last4=Prüfer |first4=K. |last5=Kelso |first5=J. |last6=Pääbo |first6=S. |author-link6=Svante Pääbo |last7=Patterson |first7=N. |last8=Reich |first8=D. |title=The genomic landscape of Neanderthal ancestry in present-day humans |journal=Nature |year= 2014 |volume=507 |issue=7492 |pages=354–357 |doi=10.1038/nature12961 |pmid=24476815 |pmc=4072735 |bibcode=2014Natur.507..354S}}</ref><ref>{{cite journal |doi=10.1093/molbev/msr024 |title=An X-linked haplotype of Neandertal origin is present among all non-African populations |year=2011 |last1=Yotova |first1=V. |last2=Lefebvre |first2=J.-F. |last3=Moreau |first3=C. |display-authors=3 |last4=Gbeha |first4=E. |last5=Hovhannesyan |first5=K. |last6=Bourgeois |first6=S. |last7=Bédarida |first7=S. |last8=Azevedo |first8=L. |last9=Amorim |first9=A. |last10=Sarkisian |first10=T. |last11=Avogbe |first11=P. H. |last12=Chabi |first12=N. |last13=Dicko |first13=M. H. |last14=Kou' Santa Amouzou |first14=E. S. |last15=Sanni |first15=A. |last16=Roberts-Thomson |first16=J. |last17=Boettcher |first17=B. |last18=Scott |first18=R. J. |last19=Labuda |first19=D. |journal=Molecular Biology and Evolution |volume=28 |issue=7 |pages=1957–1962 |pmid=21266489 |doi-access=free}}</ref><ref name=qiaomei2014>{{cite journal |last1=Fu |first1=Q. |last2=Li |first2=H. |last3=Moorjani |first3=P. |display-authors=3 |last4=Jay |first4=F. |last5=Slepchenko |first5=S. M. |last6=Bondarev |first6=A. A. |last7=Johnson |first7=P. L. F. |last8=Aximu-Petri |first8=A. |last9=Prüfer |first9=K. |last10=de Filippo |first10=C. |last11=Meyer |first11=M. |last12=Zwyns |first12=Ni. |last13=Salazar-García |first13=D. C. |last14=Kuzmin |first14=Y. V. |last15=Keates |first15=S. G. |last16=Kosintsev |first16=P. A. |last17=Razhev |first17=D. I. |last18=Richards |first18=M. P. |last19=Peristov |first19=N. V. |last20=Lachmann |first20=M. |last21=Douka |first21=K. |last22=Higham |first22=T. F. G. |last23=Slatkin |first23=M. |last24=Hublin |first24=J.-J. |last25=Reich |first25=D. |last26=Kelso |first26=J. |last27=Viola |first27=T. B. |last28=Pääbo |first28=S. |author-link28=Svante Pääbo |title=Genome sequence of a 45,000-year-old modern human from western Siberia |journal=Nature |year= 2014 |volume=514 |issue=7523 |pages=445–449 |doi=10.1038/nature13810 |pmid=25341783 |pmc=4753769 |bibcode=2014Natur.514..445F}}</ref><ref name="Chen Wolf Fu Li Akey"/> Various estimates exist for the proportion, such as 1–4%<ref name=green/> or 3.4–7.9% in modern Eurasians,<ref name=KLLF>{{cite journal |arxiv=1307.8263 |title=Maximum likelihood evidence for Neandertal admixture in Eurasian populations from three genomes |first1=K. |last1=Lohse |first2=L. A. F. |last2=Frantz |journal=Populations and Evolution |bibcode=2013arXiv1307.8263L |volume=1307 |year=2013 |page=8263}}</ref> or 1.8–2.4% in modern Europeans and 2.3–2.6% in modern East Asians.<ref>{{cite journal |last1=Prüfer |first1=K. |last2=de Filippo |first2=C. |last3=Grote | first3=S. |last4=Mafessoni |first4=F. |last5=Korlević |first5=P. |last6=Hajdinjak |first6=M. |title=A high-coverage Neandertal genome from Vindija Cave in Croatia |journal=Science |year=2017 |doi=10.1126/science.aao1887 |pmid=28982794 |pmc=6185897 |display-authors=etal |volume=358 |issue=6363 |pages=655–658 |bibcode=2017Sci...358..655P}}</ref> Pre-agricultural Europeans appear to have had similar, or slightly higher,<ref name="Chen Wolf Fu Li Akey"/> percentages to modern East Asians, and the numbers may have decreased in the former due to dilution with a group of people which had split off before Neanderthal [[introgression]].{{sfn|Reich|2018}}

However, dueDue to their small population and resulting reduced effectivity of natural selection, Neanderthals accumulated several weakly harmful mutations, which were introduced to and slowly selected out of the much larger modern human population; the initial hybridised population may have experienced up to a 94% reduction in fitness compared to contemporary humans. By this measure, Neanderthals may have substantially increased in fitness.<ref name=juric>{{cite journal |first1=I. |last1=Juric |first2=S. |last2=Aeschbacher |first3=G. |last3=Coop |year=2016 |title=The strength of selection against Neanderthal introgression |journal=PLOS Genetics |volume=12 |issue=11 |pages=e1006340 |doi=10.1371/journal.pgen.1006340 |pmid=27824859 |pmc=5100956 |doi-access=free }}</ref> A 2017 study focusing on archaic genes in Turkey found associations with [[coeliac disease]], [[malaria]] severity and [[Costello syndrome]].<ref>{{cite journal |first1=R. O. |last1=Taskent |first2=N. D. |last2=Alioglu |first3=E. |last3=Fer |display-authors=et al. |year=2017 |title=Variation and functional impact of Neanderthal ancestry in Western Asia |journal=Genome Biology and Evolution |volume=9 |issue=12 |pages=3516–3624 |doi=10.1093/gbe/evx216 |pmc=5751057 |pmid=29040546}}</ref>

A 2017 study reported finding that the more Neanderthal DNA a person has in their genome, the more closely the brain of the individual would resemble that of a Neanderthal. The study also found that parts of the Neanderthal brain related to tool use and visual discrimination may have also experienced evolutionary or adaptational '"trade-offs'" with the '"social brain'", as also found in scientific studies on autism.<ref>{{cite journal |last1=Gregory |first1=Michael D. |last2=Kippenhan |first2=J. Shane |last3=Eisenberg |first3=Daniel P. |last4=Kohn |first4=Philip D. |last5=Dickinson |first5=Dwight |last6=Mattay |first6=Venkata S. |last7=Chen |first7=Qiang |last8=Weinberger |first8=Daniel R. |last9=Saad |first9=Ziad S. |last10=Berman |first10=Karen F. |title=Neanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain |journal=Scientific Reports |date=24 July 2017 |volume=7 |issue=1 |page=6308 |doi=10.1038/s41598-017-06587-0 |urlpmid=https://www.nature.com/articles/s41598-017-06587-028740249 |access-datepmc=235524936 March 2024|pmcbibcode=55249362017NatSR...7.6308G }}</ref> A 2023 study also found evidence that Neanderthal [[single nucleotide polymorphism]]s (SNPs) likely play a "significant role" in autism susceptibility and heritability in autism populations across the [[United States]]. According to the study, "Although most studies on autism genomics focus on the deleterious nature of variants, there is the possibility some of these autism-associated Neanderthal SNPs have been under weak [[positive selection]]. In support, recent studies have identified genetic variants implicated in both autism and [[Heritability of IQ|high intelligence]]. Meanwhile, autistic people often perform better on tests of fluid intelligence than [[neurotypical]]s."{{Citation needed|date=April 2024|reason=previously cited a preprint}}

Another 2017 study that analyzed 68 genes associated with [[neurodevelopmental disorder]]s, including autism, found that these disorders were also affected by [[natural selection]] and interbreeding between ''Homo sapiens'' and other [[archaic human]] species. The study also recommended further research into the link between Neanderthal [[single nucleotide polymorphism]]s (SNPs) and neurodevelopmental disorders, including autism, in modern-day humans.<ref>{{cite journal |last1=Mozzi |first1=Alessandra |last2=Forni |first2=Diego |last3=Cagliani |first3=Rachele |last4=Pozzoli |first4=Uberto |last5=Clerici |first5=Mario |last6=Sironi |first6=Manuela |title=Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders |journal=Scientific Reports |date=21 July 2017 |volume=7 |issue=6116 |page=6116 |doi=10.1038/s41598-017-06440-4 |urlpmid=https://www.nature.com/articles/s41598-017-06440-428733602 |access-datepmc=235522412 March|bibcode=2017NatSR...7.6116M 2024|hdl=2434/554557 |hdl-access=free }}</ref>

A 2021 study confirmed these findings, noting that "the protective allele of rs7170637(A) [[CYFIP1]], [one of the genes associated with [[autism spectrum disorder]] (ASD)], was present in primates to Neanderthals, and reemerged in modern humans, while absent in early modern humans"; "identified significant positive selection signals in 18 ASD risk SNPs"; that "ancient genome analysis identified [[de novo mutation]]s...representing genes involved in cognitive function...and conserved evolutionary selection clusters"; and that "relative [[Gene set enrichment analysis|enrichment]] of the ASD risk SNPs from the respective evolutionary cluster or biological interaction networks may help in addressing the [[phenotype|phenotypic]] diversity in ASD", with "cognitive genomic tradeoff signatures impacting the biological networks [explaining] the paradoxical [[phenotype]]s in ASD".<ref>{{cite journal |last1=Prakash |first1=Anil |last2=Banerjee |first2=Moinak |title=Genomic selection signatures in autism spectrum disorder identifies cognitive genomic tradeoff and its relevance in paradoxical phenotypes of deficits versus potentialities |journal=Scientific Reports |date=13 May 2021 |volume=11 |issue=10245 |page=10245 |doi=10.1038/s41598-021-89798-w |pmid=33986442 |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119484/ |access-date=23 March8119484 2024|pmcbibcode=81194842021NatSR..1110245P }}</ref>

The [[MMR vaccine]] as a cause of autism is one of the most extensively debated hypotheses regarding the origins of autism. [[Andrew Wakefield]] ''et al.'' reported a study of 12 children who had autism and bowel symptoms, in some cases reportedly with onset after MMR.<ref name="Retraction2">{{cite journal |vauthors=((The Editors Of The Lancet)) |date=February 2010 |title=Retraction--Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children |journal=Lancet |volume=375 |issue=9713 |pages=445 |doi=10.1016/S0140-6736(10)60175-4 |pmid=20137807 |s2cid=26364726}} For a lay summary, see {{cite news |date=2010-02-02 |title=Lancet accepts MMR study 'false' |work=BBC News |url=http://news.bbc.co.uk/2/low/health/8493753.stm |vauthors=Triggle N}}</ref> Although the paper, which was later retracted by the journal, concluded that there was no association between the MMR vaccine and autism, Wakefield nevertheless suggested a false notion during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose.<ref name="Retraction2" /><ref name="Wakefield_1998">{{cite journal |display-authors=6 |vauthors=Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA |date=February 1998 |title=Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children |journal=Lancet |volume=351 |issue=9103 |pages=637–641 |doi=10.1016/S0140-6736(97)11096-0 <!-- note = doi was 10.1016/S0140-6736(97)11096-0 and URL was http://briandeer.com/mmr/lancet-paper.htm --> |pmid=9500320 |s2cid=439791}}{{Retracted paper|doi=10.1016/S0140-6736(10)60175-7|intentional=yes}}</ref> Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first.<ref>{{cite journal | vauthors name= Wilder-Smith AB, Qureshi K | title = "Resurgence of Measles in Europe: A Systematic Review on Parental Attitudes and Beliefs of Measles Vaccine | journal = Journal of Epidemiology and Global Health | volume = 10 | issue = 1 | pages = 46–58 | date = March 2020 | pmid = 32175710 | pmc = 7310814 | doi = 10.2991/jegh.k.191117.001 }}<"/ref><ref name="Di_Pietrantonj_2021" />

Perhaps the best-known hypothesis involving mercury and autism involves the use of the mercury-based compound [[thiomersal]], a preservative that has been phased out from most childhood [[Vaccination|vaccinationsvaccination]]s in developed countries including US and the EU.<ref>{{cite web |year=2012 |title=Vaccines, blood and biologics: thimerosal in vaccines |url=https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/ucm096228.htm#thi |access-date=October 24, 2013 |publisher=US Food and Drug Administration}}</ref> There is no scientific evidence for a causal connection between thiomersal and autism, but parental concern about a relationship between [[thiomersal and vaccines]] has led to decreasing rates of [[childhood immunizations]] and increasing likelihood of disease outbreaks.<ref>{{cite journal | vauthors name= Wilder-Smith AB, Qureshi K | title = "Resurgence of Measles in Europe: A Systematic Review on Parental Attitudes and Beliefs of Measles Vaccine | journal = Journal of Epidemiology and Global Health | volume = 10 | issue = 1 | pages = 46–58 | date = March 2020 | pmid = 32175710 | pmc = 7310814 | doi = 10.2991"/jegh.k.191117.001 }}</ref><ref>{{cite journal | vauthors name= Gidengil C, Chen C, Parker AM, Nowak S, Matthews L | title = "Beliefs around childhood vaccines in the United States: A systematic review | journal = Vaccine | volume = 37 | issue = 45 | pages = 6793–6802 | date = October 2019 | pmid = 31562000 | pmc = 6949013 | doi = 10.1016i"/j.vaccine.2019.08.068 }}</ref><ref name="Di_Pietrantonj_2021" /> In 1999, due to concern about the dose of mercury infants were being exposed to, the U.S. Public Health Service recommended that thiomersal be removed from childhood vaccines, and by 2002 the flu vaccine was the only childhood vaccine containing more than trace amounts of thimerosal. Despite this, autism rates did not decrease after the removal of thimerosal, in the US or other countries that also removed thimerosal from their childhood vaccines.<ref>{{Cite web |date=7 January 2008 |title=Mercury in vaccines as a cause of autism and autism spectrum disorders (ASDs): A failed hypothesis |url=https://sciencebasedmedicine.org/mercury-in-vaccines-and-autism-a-failed-hypothesis/ |work=Science-Based Medicine |vauthors=Gorski D}}</ref>