Dataset Information

Identification of pleiotropy at the gene level between psychiatric disorders and related traits.

ABSTRACT: Major mental disorders are highly prevalent and make a substantial contribution to the global disease burden. It is known that mental disorders share clinical characteristics, and genome-wide association studies (GWASs) have recently provided evidence for shared genetic factors as well. Genetic overlaps are usually identified at the single-marker level. Here, we aimed to identify genetic overlaps at the gene level between 7 mental disorders (schizophrenia, autism spectrum disorder, major depressive disorder, anorexia nervosa, ADHD, bipolar disorder and anxiety), 8 brain morphometric traits, 2 cognitive traits (educational attainment and general cognitive function) and 9 personality traits (subjective well-being, depressive symptoms, neuroticism, extraversion, openness to experience, agreeableness and conscientiousness, children's aggressive behaviour, loneliness) based on publicly available GWASs. We performed systematic conditional regression analyses to identify independent signals and select loci associated with more than one trait. We identified 48 genes containing independent markers associated with several traits (pleiotropy at the gene level). We also report 9 genes with different markers that show independent associations with single traits (allelic heterogeneity). This study demonstrates that mental disorders and related traits do show pleiotropy at the gene level as well as the single-marker level. The identification of these genes might be important for prioritizing further deep genotyping, functional studies, or drug targeting.

SUBMITTER: Polushina T

PROVIDER: S-EPMC8322263 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Identification of pleiotropy at the gene level between psychiatric disorders and related traits.

Polushina Tatiana T Banerjee Niladri N Giddaluru Sudheer S Bettella Francesco F Espeseth Thomas T Lundervold Astri J AJ Djurovic Srdjan S Cichon Sven S Hoffmann Per P Nöthen Markus M MM Steen Vidar M VM Andreassen Ole A OA Le Hellard Stéphanie S

Translational psychiatry 20210729 1

Major mental disorders are highly prevalent and make a substantial contribution to the global disease burden. It is known that mental disorders share clinical characteristics, and genome-wide association studies (GWASs) have recently provided evidence for shared genetic factors as well. Genetic overlaps are usually identified at the single-marker level. Here, we aimed to identify genetic overlaps at the gene level between 7 mental disorders (schizophrenia, autism spectrum disorder, major depress ...[more]

PMID: 34326310

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Project description:Little is known about the molecular underpinning of behavioral pleiotropy. The Drosophila melanogaster foraging gene is highly pleiotropic, affecting many independent larval and adult phenotypes. Included in foraging's multiple phenotypes are larval foraging path length, triglyceride levels, and food intake. foraging has a complex structure with four promoters and 21 transcripts that encode nine protein isoforms of a cGMP dependent protein kinase (PKG). We examined if foraging's complex molecular structure underlies the behavioral pleiotropy associated with this gene. Using a promotor analysis strategy, we cloned DNA fragments upstream of each of foraging's transcription start sites and generated four separate forpr-Gal4s. Supporting our hypothesis of modular function, they had discrete, restricted expression patterns throughout the larva. In the CNS, forpr1-Gal4 and forpr4-Gal4 were expressed in neurons while forpr2-Gal4 and forpr3-Gal4 were expressed in glia cells. In the gastric system, forpr1-Gal4 and forpr3-Gal4 were expressed in enteroendocrine cells of the midgut while forpr2-Gal4 was expressed in the stem cells of the midgut. forpr3-Gal4 was expressed in the midgut enterocytes, and midgut and hindgut visceral muscle. forpr4-Gal4's gastric system expression was restricted to the hindgut. We also found promoter specific expression in the larval fat body, salivary glands, and body muscle. The modularity of foraging's molecular structure was also apparent in the phenotypic rescues. We rescued larval path length, triglyceride levels (bordered on significance), and food intake of for0 null larvae using different forpr-Gal4s to drive UAS-forcDNA. In a foraging null genetic background, forpr1-Gal4 was the only promoter driven Gal4 to rescue larval path length, forpr3-Gal4 altered triglyceride levels, and forpr4-Gal4 rescued food intake. Our results refine the spatial expression responsible for foraging's associated phenotypes, as well as the sub-regions of the locus responsible for their expression. foraging's pleiotropy arises at least in part from the individual contributions of its four promoters.

Project description:BackgroundAge-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits.MethodsFor each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression.ResultsOf the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27-20.69%) and 16 of them were found to be significantly associated with AMD (Q-values < 0.01, p values from < 1.0 × 10-16 to 1.9 × 10-3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values < 0.01, p values from 1.1 × 10-7 to 3.0 × 10-4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis.ConclusionsWe demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common.

Dataset Information

Identification of pleiotropy at the gene level between psychiatric disorders and related traits.

Publications

Identification of pleiotropy at the gene level between psychiatric disorders and related traits.

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