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Increased female autosomal burden of rare copy number variants in human populations and in autism families

Molecular Psychiatry volume 20, pages 170–175 (2015)Cite this article

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Abstract

Autosomal genetic variation is presumed equivalent in males and females and makes a major contribution to disease risk. We set out to identify whether maternal copy number variants (CNVs) contribute to autism spectrum disorders (ASDs). Surprisingly, we observed a higher autosomal burden of large, rare CNVs in females in the population, reflected in, but not unique to, ASD families. Meta-analysis across control data sets confirms female excess in CNV number (P=2.1 × 10−5) and gene content (P=4.1 × 10−3). We additionally observed CNV enrichment in ASD mothers compared with control mothers (P=0.03). We speculate that tolerance for CNV burden contributes to decreased female fetal loss in the population and that ASD-specific maternal CNV burden may contribute to high sibling recurrence. These data emphasize the need for study of familial CNV risk factors in ASDs and the requirement of sex-matched comparisons.

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Acknowledgements

We acknowledge Drs Don Conrad, Jane Gitschier, Noah Zaitlen, Erika Yeh, Ousseny Zerbo and Vincent Yau for helpful discussion, Dr Ye Cheng for CNV calling in the AGRE data set and Kathryn Tsang for population comparisons based on SNP data. We thank all families who participated in and contributed to the studies and the public resources that we have used in these studies. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium, the Simons Simplex Collection (SSC) and the participating families. We acknowledge funding sources R01 ES016669 (Croen), R21 HD065273 (Weiss), SFARI 136720 (Weiss) as well as IMHRO and UCSF-REAC support (to Weiss).

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Authors and Affiliations

  1. Department of Psychiatry and Institute for Human Genetics, UCSF, San Francisco, CA, USA

    G Desachy & L A Weiss

  2. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

    L A Croen, G N Delorenze & C K Yoshida

  3. Center for Persons with Disabilities, Utah State University, Logan, UT, USA

    A R Torres

  4. California Department of Public Health, Genetic Disease Screening Program, Richmond, CA, USA

    M Kharrazi

  5. Division of Environmental and Occupational Disease Control, California Department of Public Health, Richmond, CA, USA

    G C Windham

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  1. G Desachy
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  2. L A Croen
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Correspondence to L A Weiss.

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Desachy, G., Croen, L., Torres, A. et al. Increased female autosomal burden of rare copy number variants in human populations and in autism families. Mol Psychiatry 20, 170–175 (2015). https://doi.org/10.1038/mp.2014.179

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