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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

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  1. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

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  2. A catalog of genetic loci associated with kidney function from analyses of a million individuals

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  3. Publisher Correction: Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

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  4. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

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  1. Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures

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  2. Polygenic predisposition to breast cancer and the risk of coronary artery disease

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  3. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

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  4. Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study

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  5. Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts

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  • CHD Exome+ Consortium
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Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

Original languageEnglish
JournalNature Genetics
Volume51
Issue number3
Pages (from-to)452-469
Number of pages18
ISSN1061-4036
DOIs
Publication statusPublished - 1 Mar 2019

ID: 56600479