Abstract：
: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.
journal_name
Mol Psychiatryjournal_title
Molecular psychiatryauthors
Ryan NM,Lihm J,Kramer M,McCarthy S,Morris SW,Arnau-Soler A,Davies G,Duff B,Ghiban E,Hayward C,Deary IJ,Blackwood DHR,Lawrie SM,McIntosh AM,Evans KL,Porteous DJ,McCombie WR,Thomson PAdoi
10.1038/s41380-018-0087-4subject
Has Abstractpub_date
2018-12-01 00:00:00pages
2254-2265issue
12eissn
1359-4184issn
1476-5578pii
10.1038/s41380-018-0087-4journal_volume
23pub_type
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