The Female Protective Effect in Autism Spectrum Disorder is Not Mediated by a Single Genetic Locus

Overview

Journal Mol Autism

Publisher Biomed Central

Date 2015 May 15

PMID 25973162

Citations 38

Authors

Jake Gockley

A Jeremy Willsey

Shan Dong

Joseph D Dougherty

John N Constantino

Stephan J Sanders

Affiliations

Soon will be listed here.

Abstract

Background: A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis.

Methods: To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide.

Results: No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect.

Conclusions: The results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE.

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References

Constantino J, Todd R . Autistic traits in the general population: a twin study. Arch Gen Psychiatry. 2003; 60(5):524-30. DOI: 10.1001/archpsyc.60.5.524. View

Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L . Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014; 94(5):677-94. PMC: 4067558. DOI: 10.1016/j.ajhg.2014.03.018. View

Sanders S, Murtha M, Gupta A, Murdoch J, Raubeson M, Willsey A . De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012; 485(7397):237-41. PMC: 3667984. DOI: 10.1038/nature10945. View

Carrel L, Willard H . X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005; 434(7031):400-4. DOI: 10.1038/nature03479. View

Geschwind D, Sowinski J, Lord C, Iversen P, Shestack J, Jones P . 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. PMC: 1235320. DOI: 10.1086/321292. View

Klei L, Sanders S, Murtha M, Hus V, Lowe J, Willsey A . Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism. 2012; 3(1):9. PMC: 3579743. DOI: 10.1186/2040-2392-3-9. View

Constantino J, Zhang Y, Frazier T, Abbacchi A, Law P . Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry. 2010; 167(11):1349-56. PMC: 2970737. DOI: 10.1176/appi.ajp.2010.09101470. View

Iossifov I, ORoak B, Sanders S, Ronemus M, Krumm N, Levy D . The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014; 515(7526):216-21. PMC: 4313871. DOI: 10.1038/nature13908. View

Kamio Y, Inada N, Moriwaki A, Kuroda M, Koyama T, Tsujii H . Quantitative autistic traits ascertained in a national survey of 22 529 Japanese schoolchildren. Acta Psychiatr Scand. 2012; 128(1):45-53. PMC: 3604131. DOI: 10.1111/acps.12034. View

10.

Levy D, Ronemus M, Yamrom B, Lee Y, Leotta A, Kendall J . 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. View

11.

Li Q, Yu K . Improved correction for population stratification in genome-wide association studies by identifying hidden population structures. Genet Epidemiol. 2007; 32(3):215-26. DOI: 10.1002/gepi.20296. View

12.

Fischbach G, Lord C . The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 2010; 68(2):192-5. DOI: 10.1016/j.neuron.2010.10.006. View

13.

De Rubeis S, He X, Goldberg A, Poultney C, Samocha K, Cicek A . Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014; 515(7526):209-15. PMC: 4402723. DOI: 10.1038/nature13772. View

14.

. Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ. 2012; 61(3):1-19. View

15.

Constantino J, Todd R . Intergenerational transmission of subthreshold autistic traits in the general population. Biol Psychiatry. 2005; 57(6):655-60. DOI: 10.1016/j.biopsych.2004.12.014. View

16.

Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G . Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum Mol Genet. 2012; 21(21):4781-92. PMC: 3471395. DOI: 10.1093/hmg/dds301. View

17.

Fombonne E . Epidemiology of pervasive developmental disorders. Pediatr Res. 2009; 65(6):591-8. DOI: 10.1203/PDR.0b013e31819e7203. View

18.

Dong S, Walker M, Carriero N, DiCola M, Willsey A, Ye A . De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Cell Rep. 2014; 9(1):16-23. PMC: 4194132. DOI: 10.1016/j.celrep.2014.08.068. View

19.

Gaugler T, Klei L, Sanders S, Bodea C, Goldberg A, Lee A . Most genetic risk for autism resides with common variation. Nat Genet. 2014; 46(8):881-5. PMC: 4137411. DOI: 10.1038/ng.3039. View

20.

Kim Y, Leventhal B, Koh Y, Fombonne E, Laska E, Lim E . 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. View