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Shared genetic underpinnings of childhood obesity and adult cardiometabolic diseases.

ABSTRACT: BACKGROUND:Obesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic traits using a unified statistical approach that integrates pleiotropy and functional annotation data. RESULTS:Pleiotropic genetic effects were significantly abundant in 13 out of 15 childhood BMI-adult cardiometabolic trait tests (P?

SUBMITTER: Tekola-Ayele F

PROVIDER: S-EPMC6449964 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Shared genetic underpinnings of childhood obesity and adult cardiometabolic diseases.

Tekola-Ayele Fasil F Lee Anthony A Workalemahu Tsegaselassie T Sánchez-Pozos Katy K

Human genomics 20190404 1

<h4>Background</h4>Obesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic trai ...[more]

PMID: 30947744

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Project description:Epidemiological and clinical studies have found associations between depression and cardiovascular disease risk factors, and coronary artery disease patients with depression have worse prognosis. The genetic relationship between depression and these cardiovascular phenotypes is not known. We here investigated overlap at the genome-wide level and in individual loci between depression, coronary artery disease and cardiovascular risk factors. We used the bivariate causal mixture model (MiXeR) to quantify genome-wide polygenic overlap and the conditional/conjunctional false discovery rate (pleioFDR) method to identify shared loci, based on genome-wide association study summary statistics on depression (n = 450,619), coronary artery disease (n = 502,713) and nine cardiovascular risk factors (n = 204,402-776,078). Genetic loci were functionally annotated using FUnctional Mapping and Annotation (FUMA). Of 13.9K variants influencing depression, 9.5K (SD 1.0K) were shared with body-mass index. Of 4.4K variants influencing systolic blood pressure, 2K were shared with depression. ConjFDR identified 79 unique loci associated with depression and coronary artery disease or cardiovascular risk factors. Six genomic loci were associated jointly with depression and coronary artery disease, 69 with blood pressure, 49 with lipids, 9 with type 2 diabetes and 8 with c-reactive protein at conjFDR < 0.05. Loci associated with increased risk for depression were also associated with increased risk of coronary artery disease and higher total cholesterol, low-density lipoprotein and c-reactive protein levels, while there was a mixed pattern of effect direction for the other risk factors. Functional analyses of the shared loci implicated metabolism of alpha-linolenic acid pathway for type 2 diabetes. Our results showed polygenic overlap between depression, coronary artery disease and several cardiovascular risk factors and suggest molecular mechanisms underlying the association between depression and increased cardiovascular disease risk.

Project description:Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. Understanding the genetic architecture of this comorbidity could be improved by focusing on intermediate traits that show positive genetic correlation with the disorders. Thus, we aimed to characterize the shared vs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD) -beyond genetic correlation, and boost discovery for jointly-associated loci. Summary statistics for MOOD (a binary measure of the tendency to report frequent mood swings), AC (number of standard drinks over a typical consumption week) and AUD GWASs (Ns > 200,000) were analyzed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD. To do so, we used a newly established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly associated genomic loci, which were mapped to genes and biological functions. MOOD was highly polygenic (10.4k single nucleotide polymorphisms, SNPs, SD = 2k) compared to AC (4.9k SNPs, SD = 0.6k) and AUD (4.3k SNPs, SD = 2k). The polygenic overlap of MOOD and AC was twice that of MOOD and AUD (98% vs. 49%), with opposite genetic correlation (-0.2 vs. 0.23), as confirmed in independent samples. MOOD&AUD associated SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 jointly associated loci, fifteen were novel for MOOD, AC and AUD. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated partly shared biological underpinnings, yet, clearly distinct functional patterns between MOOD&AC and MOOD&AUD, suggesting new mechanisms for the comorbidity of AUD with mood disorders.

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Shared genetic underpinnings of childhood obesity and adult cardiometabolic diseases.

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Shared genetic underpinnings of childhood obesity and adult cardiometabolic diseases.

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