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Whole Exome Sequencing in First Degree Cousin Pairs with Early Age-at-Onset Bipolar Disorder

Thursday, October 11, 2012 — Poster Session III

10:00 a.m. – Noon

Natcher Conference Center, Building 45



* FARE Award Winner


  • DTW Chen
  • N Akula
  • L Hou
  • CJM Steele
  • L Kassem
  • BiGS Consortium
  • FJ McMahon


Individuals with bipolar disorder(BD), a top 10 WHO burden in 2000, are afflicted with suicides and disabilities. Though BD is highly heritable, single-nucleotide polymorphism(SNP) markers identified by genome-wide association studies(GWAS) account for little of the heritability. Identification of rarer genetic variants by Next-Generation Sequencing(NGS) technologies in first-degree cousins enriched for BD may be a good approach. We identified 4 first-cousin pairs with BD beginning before age 16 for whole-exome NGS with SOLiD technology. Fragment libraries and exome capture were performed with Agilent SureSelect50MB array. Duplicate removal and re-calibration were performed using PICARD & GATK, respectively. 65-80M reads were mapped to the reference genome(hg19) and filtered for minor allele frequencies>10% in 1000 Genomes Database. Using BEAGLE IBD, ~10K reads were mapped to genomic regions shared identical-by-descent(IBD) between cousins. The proportion of variants shared IBD by cousins exceeded that predicted by relatedness alone(150-176%). Within each pair, ~5000 variants were shared. Diminishing across multiple pairs, ~147 variants were shared in all 4 pairs. Among these were 13 uncommon non-synonymous variants in 8 genes: ACACB,ALPK2,CR1L,GRK7,KCNMB1,PRB4,TRIM22,OR7A2P. KCNMB1 is located on chromosome 5q34, near a previously identified top hit from our early-onset BD GWAS. NGS of first-cousins with early-onset BD suggests possible targets for future studies.

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