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Molecular Autism
Published in: Molecular Autism 1/2015

Open Access 01-12-2015 | Research

Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins

Authors: Donna M Werling, Daniel H Geschwind

Published in: Molecular Autism | Issue 1/2015

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Abstract

Background

Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. However, reported ASD recurrence rates have not demonstrated significantly increased risk to siblings of affected girls. Here, we characterize recurrence patterns in multiplex families from the Autism Genetics Resource Exchange (AGRE) to determine if risk in these families follows a female protective model.

Methods

We assess recurrence rates and quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We consider the first two affected children per family, and one randomly selected autistic twin per pair, as probands. We then compare recurrence rates and phenotypes between males and females and between twin pairs or families with at least one female proband (female-containing (FC)) versus those with only male probands (male-only (MO)).

Results

Among children born after two probands, we observe significantly higher recurrence in males (47.5%) than in females (21.1%; relative risk, RR = 2.25; adjusted P = 6.22e−08) and in siblings of female (44.3%) versus siblings of male probands (30.4%; RR = 1.46; adj. P = 0.036). This sex-differential recurrence is also robust in dizygotic twin pairs (males = 61.5%, females = 19.1%; RR = 3.23; adj. P = 7.66e−09). Additionally, we find a significant negative relationship between interbirth interval and ASD recurrence that is driven by children in MO families.

Conclusions

By classifying families as MO or FC using two probands instead of one, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, a significant sex difference in risk to children within FC families suggests that female protective mechanisms are still operative in families carrying high genetic risk loads. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk is consistent with a potentially greater contribution from environmental factors in males versus higher genetic risk in affected females and their families. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.
Appendix
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Literature
1.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.CrossRef
2.
Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators CfDCaP. Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ. 2014;63(2):1–21.
3.
Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25(1):63–77.CrossRefPubMed
4.
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 Psychiatry. 2011;68(11):1095–102. doi:10.1001/archgenpsychiatry.2011.76.CrossRefPubMed
5.
Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry. 2010;167(11):1349–56. doi:10.1176/appi.ajp.2010.09101470.CrossRefPubMedCentralPubMed
6.
Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, et al. Recurrence risk for autism spectrum disorders: a baby siblings research consortium study. Pediatrics. 2011;128(3):e488–95. doi:10.1542/peds. 2010-2825.PubMedCentralPubMed
7.
Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, et al. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74(2):285–99. doi:10.1016/j.neuron.2012.04.009.CrossRefPubMedCentralPubMed
8.
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. doi:10.1016/j.neuron.2011.05.015.CrossRefPubMed
9.
Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485(7397):242–5. doi:10.1038/nature11011.CrossRefPubMedCentralPubMed
10.
O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485(7397):246–50. doi:10.1038/nature10989.CrossRefPubMedCentralPubMed
11.
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. doi:10.1038/nature09146.CrossRefPubMedCentralPubMed
12.
Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70(5):863–85. doi:10.1016/j.neuron.2011.05.002.CrossRefPubMedCentralPubMed
13.
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485(7397):237–41. doi:10.1038/nature10945.CrossRefPubMedCentralPubMed
14.
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. doi:10.1126/science.1138659.CrossRefPubMedCentralPubMed
15.
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. doi:10.1038/ng.3039
16.
Stein JL, Parikshak NN, Geschwind DH. Rare inherited variation in autism: beginning to see the forest and a few trees. Neuron. 2013;77(2):209–11. doi:10.1016/j.neuron.2013.01.010.CrossRefPubMedCentralPubMed
17.
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. doi:10.1093/hmg/ddq307.CrossRefPubMedCentralPubMed
18.
Cantor RM, Kono N, Duvall JA, Alvarez-Retuerto A, Stone JL, Alarcon M, et al. Replication of autism linkage: fine-mapping peak at 17q21. Am J Hum Genet. 2005;76(6):1050–6. doi:10.1086/430278.CrossRefPubMedCentralPubMed
19.
Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D, et al. A genomewide screen for autism susceptibility loci. Am J Hum Genet. 2001;69(2):327–40.CrossRefPubMedCentralPubMed
20.
McCauley JL, Li C, Jiang L, Olson LM, Crockett G, Gainer K, et al. Genome-wide and ordered-subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet. 2005;6:1. doi:10.1186/1471-2350-6-1.CrossRefPubMedCentralPubMed
21.
Stone JL, Merriman B, Cantor RM, Yonan AL, Gilliam TC, Geschwind DH, et al. Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet. 2004;75(6):1117–23. doi:10.1086/426034.CrossRefPubMedCentralPubMed
22.
Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39(3):319–28. doi:10.1038/ng1985.CrossRefPubMed
23.
Wang K, Zhang H, Ma D, 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. doi:10.1038/nature07999.CrossRefPubMedCentralPubMed
24.
Weiss LA, Arking DE, Daly MJ, Chakravarti A. A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009;461(7265):802–8. doi:10.1038/nature08490.CrossRefPubMedCentralPubMed
25.
Werling DM, Lowe JK, Luo R, Cantor RM, Geschwind DH. Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder. Molecular autism. 2014;5(1):13. doi:10.1186/2040-2392-5-13.CrossRefPubMedCentralPubMed
26.
Yonan AL, Alarcon M, Cheng R, Magnusson PK, Spence SJ, Palmer AA, et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet. 2003;73(4):886–97.CrossRefPubMedCentralPubMed
27.
Ronemus M, Iossifov I, Levy D, Wigler M. The role of de novo mutations in the genetics of autism spectrum disorders. Nat Rev Genet. 2014;15(2):133–41. doi:10.1038/nrg3585.CrossRefPubMed
28.
Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, et al. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci U S A. 2007;104(31):12831–6. doi:10.1073/pnas.0705803104.CrossRefPubMedCentralPubMed
29.
Reich R, Cloninger CR, Guze SB. The multifactorial model of disease transmission: I. Description of the model and its use in psychiatry. Br J Psychiatry J Ment Sci. 1975;127:1–10.CrossRef
30.
Tsai L, Stewart MA, August G. Implication of sex differences in the familial transmission of infantile autism. J Autism Dev Disord. 1981;11(2):165–73.CrossRefPubMed
31.
32.
33.
Robinson EB, Lichtenstein P, Anckarsater H, Happe F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proc Natl Acad Sci U S A. 2013;110(13):5258–62. doi:10.1073/pnas.1211070110.CrossRefPubMedCentralPubMed
34.
Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Hum Genet. 2014;94(3):415–25. doi:10.1016/j.ajhg.2014.02.001.CrossRefPubMedCentralPubMed
35.
Lajonchere CM, Consortium A. Changing the landscape of autism research: the autism genetic resource exchange. Neuron. 2010;68(2):187–91. doi:10.1016/j.neuron.2010.10.009.CrossRefPubMedCentralPubMed
36.
Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P, et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet. 2001;69(2):463–6. doi:10.1086/321292.CrossRefPubMedCentralPubMed
37.
Volkmar FR, Szatmari P, Sparrow SS. Sex differences in pervasive developmental disorders. J Autism Dev Disord. 1993;23(4):579–91.CrossRefPubMed
38.
Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C. Prevalence of autism in a US metropolitan area. JAMA. 2003;289(1):49–55.CrossRefPubMed
39.
Sparrow SS, Balla DA, Cicchetti DV. Vineland adaptive behavior scales: interview edition, survey form manual. Circle Pines, MN: American Guidance Service; 1984.
40.
Cheslack-Postava K, Liu K, Bearman PS. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics. 2011;127(2):246–53. doi:10.1542/peds. 2010-2371.CrossRefPubMedCentralPubMed
41.
Gunnes N, Suren P, Bresnahan M, Hornig M, Lie KK, Lipkin WI, et al. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013;24(6):906–12. doi:10.1097/01.ede.0000434435.52506.f5.CrossRefPubMed
42.
Risch N, Hoffmann TJ, Anderson M, Croen LA, Grether JK, Windham GC. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am J Psychiatry. 2014. doi:10.1176/appi.ajp.2014.13101359
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. doi:10.1038/nature11396.CrossRefPubMedCentralPubMed
44.
Banach R, Thompson A, Szatmari P, Goldberg J, Tuff L, Zwaigenbaum L, et al. Brief report: relationship between non-verbal IQ and gender in autism. J Autism Dev Disord. 2009;39(1):188–93. doi:10.1007/s10803-008-0612-4.CrossRefPubMed
45.
46.
Dunn LM, Bulheller S, Häcker H. Peabody picture vocabulary test. Circle Pines, MN: American Guidance Service; 1965.
47.
Raven JC, De Lemos MM. Standard progressive matrices. London: Lewis; 1958.
48.
Constantino JN. Social responsiveness scale manual. Western Psychological Services: Los Angeles; 2012.
49.
Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, et al. SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet. 2012;90(5):879–87. doi:10.1016/j.ajhg.2012.03.017.CrossRefPubMedCentralPubMed
50.
Tropeano M, Ahn JW, Dobson RJ, Breen G, Rucker J, Dixit A, et al. Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders. PLoS One. 2013;8(4):e61365. doi:10.1371/journal.pone.0061365.CrossRefPubMedCentralPubMed
51.
Conde-Agudelo A, Rosas-Bermudez A, Castano F, Norton MH. Effects of birth spacing on maternal, perinatal, infant, and child health: a systematic review of causal mechanisms. Stud Fam Plann. 2012;43(2):93–114.CrossRefPubMed
52.
Gronborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA pediatrics. 2013;167(10):947–53. doi:10.1001/jamapediatrics.2013.2259.CrossRefPubMed
53.
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311(17):1770–7. doi:10.1001/jama.2014.4144.CrossRefPubMedCentralPubMed
54.
Giarelli E, Wiggins LD, Rice CE, Levy SE, Kirby RS, Pinto-Martin J, et al. Sex differences in the evaluation and diagnosis of autism spectrum disorders among children. Disabil Health J. 2010;3(2):107–16. doi:10.1016/J.Dhjo.2009.07.001.
55.
Dworzynski K, Ronald A, Bolton P, Happe F. How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders? J Am Acad Child Adolesc Psychiatry. 2012;51(8):788–97. doi:10.1016/J.Jaac.2012.05.018.CrossRefPubMed
56.
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. doi:10.1176/appi.ajp.2011.10101532.CrossRefPubMed
57.
Mattila ML, Kielinen M, Linna SL, Jussila K, Ebeling H, Bloigu R, et al. Autism spectrum disorders according to DSM-IV-TR and comparison with DSM-5 draft criteria: an epidemiological study. J Am Acad Child Adolesc Psychiatry. 2011;50(6):583–92. doi:10.1016/j.jaac.2011.04.001. e511.CrossRefPubMed
58.
Zwaigenbaum L, Bryson SE, Szatmari P, Brian J, Smith IM, Roberts W, et al. Sex differences in children with autism spectrum disorder identified within a high-risk infant cohort. J Autism Dev Disord. 2012;42(12):2585–96. doi:10.1007/s10803-012-1515-y.CrossRefPubMed
Metadata
Title
Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins
Authors
Donna M Werling
Daniel H Geschwind
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2015
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-015-0004-5

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