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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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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294736/
https://www.ncbi.nlm.nih.gov/pubmed/29880880
http://dx.doi.org/10.1038/s41380-018-0087-4
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author 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.
author_facet 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.
author_sort Ryan, Niamh M.
collection PubMed
description 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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spelling pubmed-62947362018-12-17 DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders 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. Mol Psychiatry Immediate Communication 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. Nature Publishing Group UK 2018-06-07 2018 /pmc/articles/PMC6294736/ /pubmed/29880880 http://dx.doi.org/10.1038/s41380-018-0087-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Immediate Communication
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.
DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
title DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
title_full DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
title_fullStr DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
title_full_unstemmed DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
title_short DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
title_sort dna sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders
topic Immediate Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294736/
https://www.ncbi.nlm.nih.gov/pubmed/29880880
http://dx.doi.org/10.1038/s41380-018-0087-4
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