TY - JOUR
T1 - DNA sequence level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
AU - Ryan, Niamh M.
AU - Lihm, Jayon
AU - Kramer, Melissa
AU - McCarthy, Shane
AU - Morris, Stewart
AU - Arnau-Soler, Aleix
AU - Davies, Gail
AU - Duff, Barbara
AU - Ghiban, Elena
AU - Hayward, Caroline
AU - Deary, Ian J.
AU - Blackwood, Douglas H. R.
AU - Lawrie, Stephen M.
AU - McIntosh, Andrew M.
AU - Evans, Kathryn L
AU - Porteous, David J
AU - McCombie, W. Richard
AU - Thomson, Pippa A
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
U2 - 10.1038/s41380-018-0087-4
DO - 10.1038/s41380-018-0087-4
M3 - Article
C2 - 29880880
SN - 1359-4184
VL - 23
SP - 2254
EP - 2265
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 12
ER -