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

Ryan, N. M., Lihm, J., Kramer, M., McCarthy, S., Morris, S. W., Arnau-Soler, A., Davies, G., Duff, B., Ghiban, E., Hayward, C., Deary, I. J., Blackwood, D. H. R., Lawrie, S. M., McIntosh, A. M., Evans, K. L., Porteous, D. J., McCombie, W. R., Thomson, P. A. (June 2018) DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders. Mol Psychiatry, 23 (12). pp. 2254-2285. ISSN 1359-4184

URL: https://www.ncbi.nlm.nih.gov/pubmed/29880880
DOI: 10.1038/s41380-018-0087-4


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.

Item Type: Paper
Subjects: diseases & disorders > mental disorders
Investigative techniques and equipment > assays > genome wide association studies
Investigative techniques and equipment > assays > next generation sequencing
CSHL Authors:
Communities: CSHL labs > McCombie lab
Depositing User: Matt Covey
Date: 7 June 2018
Date Deposited: 14 Jun 2018 15:23
Last Modified: 20 Sep 2019 18:39
PMCID: PMC6294736
Related URLs:
URI: https://repository.cshl.edu/id/eprint/36739

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