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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Bibliographic Details
Published in:Molecular psychiatry Vol. 23; no. 12; pp. 2254 - 2265
Main Authors: 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
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.12.2018
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:1359-4184
1476-5578
1476-5578
DOI:10.1038/s41380-018-0087-4