An Overview of Genetic and Environmental Risk of Autism Spectrum Disorder

Jianjun Ou1, Ruiting Liu2, Yidong Shen1, Kun Xia2, Jingping Zhao1

1Department of Psychiatry & Mental Health Institute of the Second Xiangya Hospital, Central South University, the China National Clinical Research Center for Mental Health Disorders, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Changsha, Hunan, China

2Center for Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, China

Received October 8, 2018; Accepted December 6, 2018


Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder typically diagnosed in children in the first few years of life. Genetic studies have demonstrated a moderate to high heritability of ASD, but only a limited number of single nucleotide polymorphisms (SNPs) have been identified. Meanwhile, numerous single de novo rare variants and copy number variations have been detected in patients with ASD, which are likely caused by environmental factors. Here we provide an overview of genetic and environmental factors that may contribute to the risk of ASD and we recommend that further study should be focused on both genes and environmental factors, as well as their interactions with the expectation that epigenetic studies will lead to understanding the link between the environment and risk of ASD.


Genetic association;environmental risk factors; autism spectrum disorder

Copyright 2019 by the Global Clinical and Translational Research.

How to cite this article:

Ou J, Liu R, Shen Y, Xia K, Zhao J. An overview on genetic and environmental risk of Autism Spectrum Disorder. Glob Clin Transl Res. 2019;1(1):37-44. DOI:10.36316/gcatr.01.0005.


1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM5), 5th ed. Washington, DC (US): American Psychiatric Association Publishing; 2013.

2. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383(9920):896-910.

3. Buescher AV, Cidav Z, Knapp M, Mandell DS. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 2014; 168 (8):721-8.

4. Ou JJ, Shi LJ, Xun GL, Chen C, Wu RR, Luo XR, et al. Employment and financial burden of families with preschool children diagnosed with autism spectrum disorders in urban China: results from a descriptive study. BMC Psychiatry. 2015;15:3.

5. Lotter V. Epidemiology of autistic conditions in young children. Social psychiatry. 1966;1(3):124-35.

6. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C, et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5(3):160-79.

7. Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011;168(9):904-12.

8. Saemundsen E, Magnusson P, Georgsdottir I, Egilsson E, Rafnsson V. Prevalence of autism spectrum disorders in an Icelandic birth cohort. BMJ Open. 2013;3(6):e002748.

9. Russell G, Rodgers LR, Ukoumunne OC, Ford T. Prevalence of parent-reported ASD and ADHD in the UK: findings from the Millennium Cohort Study. J Autism Dev Disord. 2014; 44(1):31-40.

10. Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. Mmwr Surveill Summ. 2018;67(6):1-23.

11. Hansen SN, Schendel DE, Parner ET. Explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices. JAMA Pediatr. 2015;169(1):56-62.

12. Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol. 2010; 23(2): 103-10.

13. Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, et al. The changing epidemiology of autism spectrum disorders. Annu Rev Public Health. 2017; 38:81-102.

14. Colvert E, Tick B, McEwen F, Stewart C, Curran SR, Woodhouse E, et al. Heritability of autism spectrum disorder in a UK population-based twin sample. JAMA Psychiatry. 2015; 72(5):415-23.

15. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311(17):1770-7.

16. Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, et al. Most genetic risk for autism resides with common variation. Nat Genet. 2014;46(8):881-5.

17. Wang K, Zhang HT, Ma DQ, Bucan M, Glessner JT, Abrahams BS, et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009;459(7246): 528-33.

18. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316 (5823):445-9.

19. O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43(6):585-9.

20. Yuen RK, Thiruvahindrapuram B, Merico D, Walker S, Tammimies K, Hoang N, et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med. 2015;21(2):185-91.

21. State MW, Sestan N. The emerging biology of autism spectrum disorders. Science. 2012;337(6100): 1301-3.

22. Weiss LA, Arking DE, Consortium JHA. A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009;461(7265):802-U62.

23. Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, et al. A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet. 2010;19(20):4072-82.

24. Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, et al. Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum Mol Genet. 2012; 21(21):4781-92.

25. Cross-Disorder Group of the Psychiatric Genomics C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013; 381(9875):1371-9.

26. Xia K, Guo H, Hu Z, Xun G, Zuo L, Peng Y, et al. Common genetic variants on 1p13.2 associate with risk of autism. Mol Psychiatry. 2014;19(11):1212-9.

27. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459(7246): 569-73.

28. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466 (7304):368-72.

29. Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 2011;70(5):886-97.

30. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008; 82(2):477-88.

31. Guo H, Peng Y, Hu Z, Li Y, Xun G, Ou J, et al. Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort. Sci Rep. 2017;7: 44155.

32. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515 (7526): 216-21.

33. Muers M. Human genetics: Fruits of exome sequencing for autism. Nature reviews Genetics. 2012;13 (6):377.

34. Wang TY, Guo H, Xiong B, Stessman HAF, Wu HD, Coe BP, et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nature Communications. 2016; 7: 13316.

35. RK CY, Merico D, Bookman M, J LH, Thiruvahin-drapuram B, Patel RV, et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci. 2017; 20(4):602-11.

36. Kim YS, Leventhal BL. Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol Psychiatry. 2015;77(1): 66-74.

37. Sealey LA, Hughes BW, Sriskanda AN, Guest JR, Gibson AD, Johnson-Williams L, et al. Environmental factors in the devleopment of autism spectrum disorders. Environ Int. 2016;88:288-98.

38. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Arch Gen Psychiat. 2011;68(11):1095-102.

39. Mandy W, Lai MC. Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition. J Child Psychol Psychiatry. 2016; 57(3):271-92.

40. Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004; 61 (6):618-27.

41. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011;16(12): 1203-12.

42. Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Psy. 2012; 51(5):477-86.

43. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012;488 (7412):471-5.

44. Buizer-Voskamp JE, Blauw HM, Boks MPM, van Eijk KR, Veldink JH, Hennekam EAM, et al. Increased paternal age and the influence on burden of genomic copy number variation in the general population. Hum Genet. 2013;132 (4): 443-50.

45. Chess S. Autism in children with congenital rubella. J Autism Child Schizophr. 1971;1(1):33-47.

46. Hutton J. Does Rubella Cause Autism: A 2015 Reappraisal? Front Hum Neurosci. 2016;10:25.

47. Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10(11):643-60.

48. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16(8):469-86.

49. Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009;204(2):313-21.

50. Spann MN, Sourander A, Surcel HM, Hinkka-Yli-Salomaki S, Brown AS. Prenatal toxoplasmosis antibody and childhood autism. Autism Res. 2017; 10(5): 769-77.

51. Estes ML, McAllister AK. Maternal immune activation: Implications for neuropsychiatric disorders. Science. 2016; 353(6301):772-7.

52. Beards S, Gayer-Anderson C, Borges S, Dewey ME, Fisher HL, Morgan C. Life events and psychosis: a review and meta-analysis. Schizophr Bull. 2013; 39 (4):740-7.

53. Holtzman CW, Trotman HD, Goulding SM, Ryan AT, Macdonald AN, Shapiro DI, et al. Stress and neurodevelopmental processes in the emergence of psychosis. Neuroscience. 2013;249:172-91.

54. van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull. 2008;34(6): 1095-105.

55. Ward AJ. A comparison and analysis of the presence of family problems during pregnancy of mothers of "autistic" children and mothers of normal children. Child Psychiatry Hum Dev. 1990;20(4):279-88.

56. Beversdorf DQ, Manning SE, Hillier A, Anderson SL, Nordgren RE, Walters SE, et al. Timing of prenatal stressors and autism. J Autism Dev Disord. 2005; 35(4):471-8.

57. Maimburg RD, Vaeth M. Perinatal risk factors and infantile autism. Acta Psychiatr Scand. 2006;114(4): 257-64.

58. Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013;346:f2059.

59. El Marroun H, White TJ, van der Knaap NJ, Homberg JR, Fernandez G, Schoemaker NK, et al. Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children. Br J Psychiatry. 2014;205(2):95-102.

60. Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders. Arch Gen Psychiat. 2011;68 (11): 1104-12.

61. Sorensen MJ, Gronborg TK, Christensen J, Parner ET, Vestergaard M, Schendel D, et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol. 2013;5:449-59.

62. Hviid A, Melbye M, Pasternak B. Use of Selective Serotonin Reuptake Inhibitors during Pregnancy and Risk of Autism. New Engl J Med. 2013;369 (25): 2406-15.

63. Gardener H, Spiegelman D, Buka SL. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009;195(1):7-14.

64. Langridge AT, Glasson EJ, Nassar N, Jacoby P, Pennell C, Hagan R, et al. Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability. PLoS One. 2013; 8(1):e50963.

65. Mahoney AD, Minter B, Burch K, Stapel-Wax J. Autism spectrum disorders and prematurity: a review across gestational age subgroups. Adv Neonatal Care. 2013;13 (4): 247-51.

66. Limperopoulos C, Bassan H, Sullivan NR, Soul JS, Robertson RL, Jr., Moore M, et al. Positive screening for autism in expreterm infants: prevalence and risk factors. Pediatrics. 2008;121(4):758-65.

67. Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Autism spectrum disorders in extremely preterm children. Journal of Pediatrics. 2010; 156 (4):525-U27.

68. Schieve LA, Tian LH, Baio J, Rankin K, Rosenberg D, Wiggins L, et al. Population attributable fractions for three perinatal risk factors for autism spectrum disorders, 2002 and 2008 autism and developmental disabilities monitoring netwo-rk. Ann Epidemiol. 2014;24(4):260-6.

69. Hultman CM, Sparen P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology. 2002; 13(4):417-23.

70. Feng XL, Xu L, Guo Y, Ronsmans C. Factors influencing rising caesarean section rates in China between 1988 and 2008. Bulletin of the World Health Organization. 2012;90 (1):30-9.

71. Guinchat V, Thorsen P, Laurent C, Cans C, Bodeau N, Cohen D. Pre-, peri- and neonatal risk factors for autism. Acta Obstet Gynecol Scand. 2012;91(3):287-300.

72. Dickerson AS, Rahbar MH, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, et al. Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic. Environ Monit Assess. 2016;188 (7): 407.

73. Fujiwara T, Morisaki N, Honda Y, Sampei M, Tani Y. Chemi-cals, Nutrition, and Autism Spectrum Disorder: A Mini-Review. Front Neurosci. 2016;10:174.

74. Kalkbrenner AE, Schmidt RJ, Penlesky AC. Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence. Curr Probl Pediatr Adolesc Health Care. 2014; 44(10):277-318.

75. Flores-Pajot MC, Ofner M, Do MT, Lavigne E, Villeneuve PJ. Childhood autism spectrum disorders and exposure to nitrogen dioxide, and particulate matter air pollution: A review and meta-analysis. Environ Res. 2016;151:763-76.

76. Gong T, Dalman C, Wicks S, Dal H, Magnusson C, Lundholm C, et al. Perinatal exposure to traffic-related air pollution and autism spectrum disorders. Environ Health Perspect. 2017;125(1):119-26.

77. Sealey LA, Hughes BW, Pestaner JP, Steinemann A, Pace DG, Bagasra O. Environmental factors may contribute to autism development and male bias: Effects of fragrances on developing neurons. Environmental Research. 2015;142:731-8.

78. Knickmeyer RC, Baron-Cohen S. Fetal testosterone and sex differences in typical social development and in autism. J Child Neurol. 2006;21(10):825-45.

79. Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G, et al. Gene x Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014;5:53.

80. Hertz-Picciotto I, Croen LA, Hansen R, Jones CR, van de Water J, Pessah IN. The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ Health Perspect. 2006;114(7): 1119 -25.

81. Kim D, Volk H, Girirajan S, Pendergrass S, Hall MA, Verma SS, et al. The joint effect of air pollution exposure and copy number variation on risk for autism. Autism Res. 2017;10 (9):1470-80.