An examination of multiple classes of rare variants in extended families with bipolar disorder

Transl Psychiatry. 2018 Mar 13;8(1):65. doi: 10.1038/s41398-018-0113-y.

Abstract

Bipolar disorder (BD) is a complex psychiatric condition with high heritability, the genetic architecture of which likely comprises both common variants of small effect and rare variants of higher penetrance, the latter of which are largely unknown. Extended families with high density of illness provide an opportunity to map novel risk genes or consolidate evidence for existing candidates, by identifying genes carrying pathogenic rare variants. We performed whole-exome sequencing (WES) in 15 BD families (117 subjects, of whom 72 were affected), augmented with copy number variant (CNV) microarray data, to examine contributions of multiple classes of rare genetic variants within a familial context. Linkage analysis and haplotype reconstruction using WES-derived genotypes enabled exclusion of false-positive single-nucleotide variants (SNVs), CNV inheritance estimation, de novo variant identification and candidate gene prioritization. We found that rare predicted pathogenic variants shared among ≥3 affected relatives were overrepresented in postsynaptic density (PSD) genes (P = 0.002), with no enrichment in unaffected relatives. Genome-wide burden of likely gene-disruptive variants was no different in affected vs. unaffected relatives (P = 0.24), but correlated significantly with age of onset (P = 0.017), suggesting that a high disruptive variant burden may expedite symptom onset. The number of de novo variants was no different in affected vs. unaffected offspring (P = 0.89). We observed heterogeneity within and between families, with the most likely genetic model involving alleles of modest effect and reduced penetrance: a possible exception being a truncating X-linked mutation in IRS4 within a family-specific linkage peak. Genetic approaches combining WES, CNV and linkage analyses in extended families are promising strategies for gene discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Bipolar Disorder / genetics*
  • DNA Copy Number Variations / genetics*
  • Exome Sequencing*
  • Family
  • Female
  • Genetic Linkage / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Insulin Receptor Substrate Proteins / genetics
  • Male
  • Nerve Tissue Proteins / genetics*
  • Pedigree*
  • Polymorphism, Single Nucleotide

Substances

  • IRS4 protein, human
  • Insulin Receptor Substrate Proteins
  • Nerve Tissue Proteins
  • postsynaptic density proteins