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

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 fam...

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Vydané v:	Molecular psychiatry Ročník 23; číslo 12; s. 2254 - 2265
Hlavní autori:	Ryan, Niamh M, Lihm, Jayon, Kramer, Melissa, McCarthy, Shane, Morris, Stewart W, Arnau-Soler, Aleix, Davies, Gail, Duff, Barbara, Ghiban, Elena, Hayward, Caroline, Deary, Ian J, Blackwood, Douglas H R, Lawrie, Stephen M, McIntosh, Andrew M, Evans, Kathryn L, Porteous, David J, McCombie, W Richard, Thomson, Pippa A
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England Nature Publishing Group 01.12.2018
Predmet:	Adult Alleles Behavior disorders Cognition Contactins - genetics Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics Disc1 protein Family - psychology Female Gene frequency Gene Frequency - genetics Genetic diversity Genetic Linkage - genetics Genetic Predisposition to Disease - genetics Genetic Testing Genome-Wide Association Study Genomes Genomics Genotype Heritability Humans Linkage analysis Lod Score Male Mental disorders Mental Disorders - genetics Mental Disorders - physiopathology Middle Aged Mood Disorders - genetics Multifactorial Inheritance Nerve Tissue Proteins - genetics Neuroimaging Nucleotide sequence Pedigree Phenotype Phenotypes Phenotypic variations Phosphodiesterase Receptor, Metabotropic Glutamate 5 - genetics Recombinant Fusion Proteins - genetics RNA, Long Noncoding RNA, Messenger - genetics Sequence Analysis, DNA - methods Translocation, Genetic
ISSN:	1359-4184, 1476-5578, 1476-5578
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1359-4184 1476-5578 1476-5578
DOI:	10.1038/s41380-018-0087-4