Dataset Information

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

ABSTRACT: 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?

SUBMITTER: Ryan NM

PROVIDER: S-EPMC6294736 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Ryan Niamh M NM Lihm Jayon J Kramer Melissa M McCarthy Shane S Morris Stewart W SW Arnau-Soler Aleix A Davies Gail G Duff Barbara B Ghiban Elena E Hayward Caroline C Deary Ian J IJ Blackwood Douglas H R DHR Lawrie Stephen M SM McIntosh Andrew M AM Evans Kathryn L KL Porteous David J DJ McCombie W Richard WR Thomson Pippa A PA

Molecular psychiatry 20180607 12

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 ...[more]

PMID: 29880880

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Project description:Plants are immobile and often face stressful environmental conditions, prompting the evolution of genes regulating environmental responses. Such evolution is achieved largely through gene duplication and subsequent divergence. One of the most important gene families involved in regulating plant environmental responses and development is the AP2/ERF superfamily; however, the evolutionary history of these genes is unclear across angiosperms and in major angiosperm families adapted to various ecological niches. Specifically, the impact on gene copy number of whole-genome duplication events occurring around the time of the origins of several plant families is unknown. Here, we present the first angiosperm-wide comparative study of AP2/ERF genes, identifying 75 Angiosperm OrthoGroups (AOGs), each derived from an ancestral angiosperm gene copy. Among these AOGs, 21 retain duplicates with increased copy number in many angiosperm lineages, while the remaining 54 AOGs tend to maintain low copy number. Further analyses of multiple species in the Brassicaceae family indicated that family-specific duplicates experienced differential selective pressures in coding regions, with some paralogs showing signs of positive selection. Further, cis regulatory elements also exhibit extensive divergence between duplicates in Arabidopsis. Moreover, comparison of expression levels suggested that AP2/ERF genes with frequently retained duplicates are enriched for broad expression patterns, offering increased opportunities for functional diversification via changes in expression patterns, and providing a mechanism for repeated duplicate retention in some AOGs. Our results represent the most comprehensive evolutionary history of the AP2/ERF gene family, and support the hypothesis that AP2/ERF genes with broader expression patterns are more likely to be retained as duplicates than those with narrower expression profiles, which could lead to a higher chance of duplicate gene subfunctionalization. The greater tendency of some AOGs to retain duplicates, allowing expression and functional divergence, may facilitate the evolution of complex signaling networks in response to new environmental conditions.

Project description:There is widespread overlap across major psychiatric disorders, and this is the case at different levels of observations, from genetic variants to brain structures and function and to symptoms. However, it remains unknown to what extent these commonalities at different levels of observation map onto each other. Here, we systematically review and compare the degree of similarity between psychiatric disorders at all available levels of observation. We searched PubMed and EMBASE between January 1, 2009 and September 8, 2022. We included original studies comparing at least four of the following five diagnostic groups: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder, with measures of similarities between all disorder pairs. Data extraction and synthesis were performed by two independent researchers, following the PRISMA guidelines. As main outcome measure, we assessed the Pearson correlation measuring the degree of similarity across disorders pairs between studies and biological levels of observation. We identified 2975 studies, of which 28 were eligible for analysis, featuring similarity measures based on single-nucleotide polymorphisms, gene-based analyses, gene expression, structural and functional connectivity neuroimaging measures. The majority of correlations (88.6%) across disorders between studies, within and between levels of observation, were positive. To identify a consensus ranking of similarities between disorders, we performed a principal component analysis. Its first dimension explained 51.4% (95% CI: 43.2, 65.4) of the variance in disorder similarities across studies and levels of observation. Based on levels of genetic correlation, we estimated the probability of another psychiatric diagnosis in first-degree relatives and showed that they were systematically lower than those observed in population studies. Our findings highlight that genetic and brain factors may underlie a large proportion, but not all of the diagnostic overlaps observed in the clinic.

Dataset Information

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

Publications

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

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