The Genetics of Autism


Autism spectrum conditions (henceforth ‘autism’) refer to a group of neurodevelopmental conditions involving difficulties in social interaction and communication and unusually repetitive and restricted behaviours and interest. Twin and family studies have established a significant heritability for autism. Autism is polygenic with variations across the allele frequency spectrum contributing to risk. Early linkage and candidate gene association studies were statistically underpowered to identify significant loci. Current genome‐wide association studies have identified significant positive genetic correlation between autism and various measures of cognition. The use of genetic microarrays and next‐generation DNA sequencing has identified tens of genes and copy number variants associated with autism. In addition, RNA microarray and sequencing studies of postmortem brain samples have identified transcriptionally altered genes and pathways in autism. Multiple lines of evidence converge on altered glial, synaptic and chromatin pathways as contributing to autism risk.

Key Concepts

  • Autism spectrum conditions (autism) represent a group of genetically and phenotypically heterogeneous neurodevelopmental conditions.
  • Autism is highly heritable as evidenced by twin studies, familial recurrence and molecular genetic analyses.
  • Autism is highly polygenic with common genetic variation, rare genetic variation and structural variation contributing to genetic risk.
  • Human DNA microarray and next‐generation sequencing of large cohorts have identified tens of associated genes and genetic loci.
  • Genome‐wide association studies point to significant heritability and genetic correlation with measures of cognition.
  • RNA sequencing and microarray studies have identified transcriptionally dysregulated genes in the autism postmortem cortex.
  • Pathway analysis across different genetic data sets identified synaptic and neuronal pathways, chromatin remodelling and a role for microglia and astrocytes.

Keywords: autism; heritability; genome‐wide association; next‐generation sequencing; linkage; transcriptomics


Alarcón M, Abrahams BS, Stone JL, et al. (2008) Linkage, association, and gene‐expression analyses identify CNTNAP2 as an autism‐susceptibility gene. American Journal of Human Genetics 82 (1): 150–159.

Anney R, Klei L, Pinto D, et al. (2010) A genome‐wide scan for common alleles affecting risk for autism. Human Molecular Genetics 19 (20): 4072–4082.

Baron‐Cohen S, Wheelwright S, Stott C, et al. (1997) Is there a link between engineering and autism? Autism 1 (1): 101–109.

Baron‐Cohen S, Wheelwright S, Hill J, et al. (2001) The “Reading the Mind in the Eyes” test revised version: a study with normal adults, and adults with Asperger syndrome or high‐functioning autism. Journal of Child Psychology and Psychiatry, and Allied Disciplines 42 (2): 241–251.

Baron‐Cohen S, Richler J, Bisarya D, et al. (2003) The systemizing quotient: an investigation of adults with Asperger syndrome or high‐functioning autism, and normal sex differences. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 358 (1430): 361–374.

Bernier R, Golzio C, Xiong B, et al. (2014) Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158 (2): 263–276.

Bourgeron T (2015) From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nature Reviews Neuroscience 16 (9): 551–563.

Bourgeron T (2016a) Current knowledge on the genetics of autism and propositions for future research. Comptes Rendus Biologies 339 (7): 300–307.

Bulik‐Sullivan B, Finucane HK, Anttila V, et al. (2015) An atlas of genetic correlations across human diseases and traits. Nature Genetics 47 (11): 1236–1241.

Carter C and Evans K (1996) Inheritance of congenital pyloric stenosis. Journal of Medical Genetics 6 (3): 233–254.

Chaste P, Klei L, Sander SJ, et al. (2015) A genome‐wide association study of autism using the Simons simplex collection: does reducing phenotypic heterogeneity in autism increase genetic homogeneity? Biological Psychiatry 77 (9): 775–784.

Chung BH‐Y, Tao VQ and Tso WW‐Y (2014) Copy number variation and autism: new insights and clinical implications. Journal of the Formosan Medical Association 113 (7): 400–408.

Clarke T‐K, Lupton MK, Fernandez‐Pujals AM, et al. (2015) Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population. Molecular Psychiatry 21 (3): 419–425.

Constantino JN, Zhang Y, Frazier T, et al. (2010) Sibling recurrence and the genetic epidemiology of autism. American Journal of Psychiatry 167 (11): 1349–1356.

Dawson G, Meltzoff AN, Osterling J, et al. (1998) Children with autism fail to orient to naturally occurring social stimuli. Journal of Autism and Developmental Disorders 28 (6): 479–485.

Durand CM, Betancur C, Boeckers TM, et al. (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics 39 (1): 25–27.

Ellis SE, Panitch R, West AB, et al. (2016) Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia. Translational Psychiatry 6 (5): e817.

Folstein S and Rutter M (1977) Infantile autism: a genetic study of 21 twin pairs. Journal of Child Psychology and Psychiatry 18 (4): 297–321.

Frans EM, Sandin S, Reichenberg A, et al. (2013) Autism risk across generations: a population‐based study of advancing grandpaternal and paternal age. JAMA Psychiatry 70 (5): 516–521.

Frazier TW, Youngstrom EA, Hardan AY, et al. (2015) Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families. Molecular Autism 6 (1): 58.

Gandal MJ, Haney J, Parikshak N, et al. (2016) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. bioRxiv.

Gaugler T, Klei L, Sanders SJ, et al. (2014) Most genetic risk for autism resides with common variation. Nature Genetics 46 (8): 881–885.

Geschwind DH and Flint J (2015) Genetics and genomics of psychiatric disease. Science 349 (6255): 1489–1494.

Geschwind DH and State MW (2015a) Gene hunting in autism spectrum disorder: on the path to precision medicine. The Lancet Neurology 14 (11): 1109–1120.

Gratten J, Wray NR, Keller MC, et al. (2014) Large‐scale genomics unveils the genetic architecture of psychiatric disorders. Nature Neuroscience 17 (6): 782–790.

Gratten J, Wray NR, Peyrot WJ, et al. (2016) Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations. Nature Genetics 48 (7): 718–724.

Grønborg TK, Schendel DE and Parner ET (2013) Recurrence of autism spectrum disorders in full‐ and half‐siblings and trends over time: a population‐based cohort study. JAMA Pediatrics 167 (10): 947–953.

Gupta S, Ellis SE, Ashar FN, et al. (2014) Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity‐dependent genes in autism. Nature Communications 5: 5748.

Helsmoortel C, Vulto‐van Silfhout AT, Coe BP, et al. (2014) A SWI/SNF‐related autism syndrome caused by de novo mutations in ADNP. Nature Genetics 46 (4): 380–384.

International Molecular Genetic Study of Autism Consortium (1998) A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Human Molecular Genetics 7 (3): 571–578.

Iossifov I, O'Roak BJ, Sanders SJ, et al. (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515 (7526): 216–221.

Jamain S, Quach H, Betancur C, et al. (2003) Mutations of the X‐linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics 34 (1): 27–29.

Jokiranta‐Olkoniemi E, Cheslack‐Postava K, Sucksdorff D, et al. (2016) Risk of psychiatric and neurodevelopmental disorders among siblings of probands with autism spectrum disorders. JAMA Psychiatry 73 (6): 622.

Jolliffe T and Baron‐Cohen S (1997) Are people with autism and Asperger syndrome faster than normal on the embedded figures test? Journal of Child Psychology and Psychiatry, and Allied Disciplines 38 (5): 527–534.

Jones W and Klin A (2013) Attention to eyes is present but in decline in 2–6‐month‐old infants later diagnosed with autism. Nature 504 (7480): 427–431.

Kanner L (1943) Autistic disturbances of affective contact. Nervous Child: Journal of Psychopathology, Psychotherapy, Mental Hygiene, and Guidance of the Child 2: 217–250.

Klei L, Sanders SJ, Murtha MT, et al. (2012) Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism 3 (1): 9.

Kong A, Frigge ML, Masson G, et al. (2012) Rate of de novo mutations and the importance of father's age to disease risk. Nature 488 (7412): 471–475.

Kosmicki JA, Samocha KE, Howrigan DP, et al. (2017) Refining the role of de novo protein‐truncating variants in neurodevelopmental disorders by using population reference samples. Nature Genetics 49 (4): 504–510.

Krumm N, O'Roak BJ, Shendure J, et al. (2014) A de novo convergence of autism genetics and molecular neuroscience. Trends in Neurosciences 37 (2): 95–105.

Lai M‐C, Lombardo MV and Baron‐Cohen S (2013) Autism. Lancet 383 (9920): 896–910.

Lek M, Karczewski KJ, Minikel EV, et al. (2016) Analysis of protein‐coding genetic variation in 60,706 humans. Nature 536 (7616): 285–291.

Leppa VM, Kravitz SN, Martin CL, et al. (2016) Rare inherited and de novo CNVs reveal complex contributions to ASD risk in multiplex families. The American Journal of Human Genetics 99 (3): 540–554.

Levy D, Ronemus M, Yamrom B, et al. (2011) Rare de novo and transmitted copy‐number variation in autistic spectrum disorders. Neuron 70 (5): 886–897.

Ma D, Salyakina D, Jaworski JM, et al. (2009) A genome‐wide association study of autism reveals a common novel risk locus at 5p14.1. Annals of Human Genetics 73 (3): 263–273.

McGrath JJ, Petersen L, Agerbo E, et al. (2014) A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry 71 (3): 301–309.

Mitra I, Tsang K, Ladd‐Acosta C, et al. (2016) Pleiotropic mechanisms indicated for sex differences in Autism. PLOS Genetics 12 (11): e1006425.

Murdoch JD, Gupta AR, Sanders SJ, et al. (2015) No evidence for association of autism with rare heterozygous point mutations in contactin‐associated protein‐like 2 (CNTNAP2), or in other contactin‐associated proteins or contactins. PLoS Genetics 11 (1): e1004852.

Neale BM, Kou Y, Liu L, et al. (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485 (7397): 242–245.

O'Roak BJ, Vives L, Fu W, et al. (2012a) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338 (6114): 1619–1622.

O'Roak BJ, Vives L, Girirajan S, et al. (2012b) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485 (7397): 246–250.

Parikshak NN, Luo R, Zhang A, et al. (2013) Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155 (5): 1008–1021.

Parikshak NN, Swarup V, Belgard TG, et al. (2016) Genome‐wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature 540: 423–427.

Peñagarikano O, Abrahams BS, Herman EI, et al. (2011) Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism‐related deficits. Cell 147 (1): 235–246.

Pinto D, Delaby E, Merico D, et al. (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. American Journal of Human Genetics 94 (5): 677–694.

Polimanti R and Gelernter J (2017) Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder. PLoS Genetics 13 (2): e1006618.

Robinson EB, Lichtenstein P, Anckarsater H, et al. (2013) Examining and interpreting the female protective effect against autistic behavior. Proceedings of the National Academy of Sciences 110 (13): 5258–5262.

Robinson EB, Samocha KE, Kosmicki JA, et al. (2014) Autism spectrum disorder severity reflects the average contribution of de novo and familial influences. Proceedings of the National Academy of Sciences 111: 15161–15165.

Robinson E, St Pourcain B, Anttila V, et al. (2016) Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nature Genetics 48 (5): 552–555.

Ronald A and Hoekstra RA (2011) Autism spectrum disorders and autistic traits: a decade of new twin studies. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 156 (3): 255–274.

De Rubeis S, He X, Goldberg AP, et al. (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515 (7526): 209–215.

Ruzich E, Allison C, Chakrabarti B, et al. (2015) Sex and STEM occupation predict autism‐spectrum quotient (AQ) scores in half a million people. PLoS One 10 (10): e0141229.

Salyakina D, Ma DQ, Jaworski JM, et al. (2010) Variants in several genomic regions associated with asperger disorder. Autism Research: Official Journal of the International Society for Autism Research 3 (6): 303–310.

Samocha KE, Robinson EB, Sanders SJ, et al. (2014) A framework for the interpretation of de novo mutation in human disease. Nature Genetics 46 (9): 944–950.

Sanders SJ, He X, Willsey AJ, et al. (2015) Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87: 1215–1233.

Sandin S, Lichtenstein P, Kuja‐Halkola R, et al. (2014) The familial risk of autism. The Journal of the American Medical Association 311 (17): 1770–1777.

Sandin S, Schendel D, Magnusson P, et al. (2015) Autism risk associated with parental age and with increasing difference in age between the parents. Molecular Psychiatry 21 (5): 693–700.

Sebat J, Lakshmi B, Malhotra D, et al. (2007) Strong association of de novo copy number mutations with autism. Science (New York, N.Y.) 316 (5823): 445–449.

Sniekers S, Stringer S, Watanabe K, et al. (2017) Genome‐wide association meta‐analysis of 78,308 individuals identifies new loci and genes influencing human intelligence. Nature Genetics 49: 1107–1112.

St Pourcain B, Whitehouse AJO, Ang WQ, et al. (2013) Common variation contributes to the genetic architecture of social communication traits. Molecular Autism 4 (1): 34.

St Pourcain B, Skuse DH, Mandy WP, et al. (2014) Variability in the common genetic architecture of social‐communication spectrum phenotypes during childhood and adolescence. Molecular Autism 5 (1): 18.

St Pourcain B, Robinson EB, Anttila V, et al. (2017) ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population‐based social communication difficulties. Molecular Psychiatry. [Epub ahead of print].

Tang G, Gudsnuk K, Kuo SH, et al. (2014) Loss of mTOR‐dependent macroautophagy causes autistic‐like synaptic pruning deficits. Neuron 83 (5): 1131–1143.

The Autism Spectrum Disorders Working Group of the Psychiatric Genomics Consortium (2017) Meta‐analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Molecular Autism 8 (1): 21.

Tick B, Bolton P, Happé F, et al. (2016) Heritability of autism spectrum disorders: a meta‐analysis of twin studies. Journal of Child Psychology and Psychiatry, and Allied Disciplines 57 (5): 585–595.

Voineagu I, Wang X, Johnston P, et al. (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474 (7351): 380–384.

Wang K, Zhang H, Ma D, et al. (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459 (7246): 528–533.

Warrier V, Chee V, Smith P, et al. (2015a) A comprehensive meta‐analysis of common genetic variants in autism spectrum conditions. Molecular Autism 6 (1): 49.

Warrier V, Chakrabarti B, Murphy L, et al. (2015b) A pooled genome‐wide association study of Asperger syndrome. PLoS One 10 (7): e0131202.

Warrier V, Toro R, Chakrabarti B, et al. (2016) Genome‐wide analyses of empathy and systemizing: heritability and correlates with sex, education, and psychiatric risk. Cold Spring Harbor Labs Journals.

Warrier V, Grasby K, Uzefovsky F, et al. (2017) Genome‐wide meta‐analysis of cognitive empathy: heritability, and correlates with sex, neuropsychiatric conditions and brain anatomy. Molecular Psychiatry. [Epub ahead of print].

Weiner DJ, Wigdor EM, Ripke S, et al. (2017) Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nature Genetics 49: 978–985.

Weiss LA, Arking DE, Daly MJ, et al. (2009) A genome‐wide linkage and association scan reveals novel loci for autism. Nature 461 (7265): 802–808.

Werling DM and Geschwind DH (2015) Recurrence rates provide evidence for sex‐differential, familial genetic liability for autism spectrum disorders in multiplex families and twins. Molecular Autism 6 (1): 27.

Wheelwright S and Baron‐Cohen S (2001) The link between autism and skills such as engineering, maths, physics and computing: a reply to Jarrold and Routh, Autism, 1998, 2(3): 281–289. Autism 5 (2): 223–227.

Wheelwright S, Auyeung B, Allison C, et al. (2010) Defining the broader, medium and narrow autism phenotype among parents using the autism spectrum quotient (AQ). Molecular Autism 1: 10.

Willsey AJ, Sanders SJ, Li M, et al. (2013) Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155 (5): 997–1007.

Xia K, Guo H, Hu Z, et al. (2014) Common genetic variants on 1p13.2 associate with risk of autism. Molecular Psychiatry 19 (11): 1212–1219.

Yuen RKC, Thiruvahindrapuram B, Merico D, et al. (2015) Whole‐genome sequencing of quartet families with autism spectrum disorder. Nature Medicine 21 (2): 185–191.

Yuen RK, Merico D, Bookman M, et al. (2017) Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nature Neuroscience 20: 602–611.

Zarrei M, MacDonald JR, Merico D, et al. (2015) A copy number variation map of the human genome. Nature Reviews Genetics 16 (3): 172–183.

Zoghbi HY and Bear MF (2012) Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harbor Perspectives in Biology 4 (3). pii: a009886.

Further Reading

Bourgeron T (2016b) Current knowledge on the genetics of autism and propositions for future research. Comptes Rendus Biologies 339 (7): 300–307.

Geschwind DH and State MW (2015b) Gene hunting in autism spectrum disorder: on the path to precision medicine. The Lancet Neurology 14 (11): 1109–1120.

Lai M‐C, Lombardo MV and Baron‐Cohen S (2013b) Autism. Lancet 383 (9920): 896–910.

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Warrier, Varun, and Baron‐Cohen, Simon(Oct 2017) The Genetics of Autism. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021455.pub2]