Measuring shared variants in cohorts of discordant siblings with applications to autism

Ye, K., Iossifov, I., Levy, D., Yamrom, B., Buja, A., Krieger, A. M., Wigler, M. (July 2017) Measuring shared variants in cohorts of discordant siblings with applications to autism. Proc Natl Acad Sci U S A, 114 (27). pp. 7073-7076. ISSN 0027-8424

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DOI: 10.1073/pnas.1700439114


We develop a method of analysis [affected to discordant sibling pairs (A2DS)] that tests if shared variants contribute to a disorder. Using a standard measure of genetic relation, test individuals are compared with a cohort of discordant sibling pairs (CDS) to derive a comparative similarity score. We ask if a test individual is more similar to an unrelated affected than to the unrelated unaffected sibling from the CDS and then, sum over such individuals and pairs. Statistical significance is judged by randomly permuting the affected status in the CDS. In the analysis of published genotype data from the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) cohorts of children with autism spectrum disorder (ASD), we find strong statistical significance that the affected are more similar to the affected than to the unaffected of the CDS (P value approximately 0.00001). Fathers in multiplex families have marginally greater similarity (P value = 0.02) to unrelated affected individuals. These results do not depend on ethnic matching or gender.

Item Type: Paper
Uncontrolled Keywords: autism discordant siblings shared variants
Subjects: bioinformatics
diseases & disorders > mental disorders > personality disorders > autism
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
CSHL Authors:
Communities: CSHL labs > Iossifov lab
CSHL labs > Levy lab
CSHL labs > Wigler lab
Depositing User: Matt Covey
Date: 3 July 2017
Date Deposited: 30 Jun 2017 18:53
Last Modified: 14 Jun 2018 19:15
PMCID: PMC5502605
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