DNA sequence level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

Niamh M. Ryan, Jayon Lihm, Melissa Kramer, Shane McCarthy, Stewart Morris, Aleix Arnau-Soler, Gail Davies, Barbara Duff, Elena Ghiban, Caroline Hayward, Ian J. Deary, Douglas H. R. Blackwood, Stephen M. Lawrie, Andrew M. McIntosh, Kathryn L Evans, David J Porteous, W. Richard McCombie, Pippa A Thomson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.
Original languageEnglish
Pages (from-to)2254–2265
Number of pages12
JournalMolecular Psychiatry
Issue number12
Early online date7 Jun 2018
Publication statusPublished - Dec 2018


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