Pleiotropic and sex-specific genetic architecture of circulating metabolic markers

Dennis van der Meer, Zillur Rahman, Aigar Ottas, Pravesh Parekh, Gleda Kutrolli, Sara Stinson, Maria Koromina, Jaroslav Rokicki, Ida Sonderby, Nadine Parker, Markos Tesfaye, Guy Hindley, Linn Rodevand, Elise Koch, Nils Steen, Jens Berg, Kevin O'Connell, Olav Smeland, Oleksandr Frei, Anders Dale, Srdjan Djurovic, Kelli Lehto, Maris Alver, Lili Milani, Alexey Shadrin, Ole Andreassen
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Abstract

Background: Metabolites in plasma form biosignatures of a range of common complex human diseases. Mapping the genetic architecture and discovering variants with pleiotropic effects across metabolites can reveal underlying mechanisms and potential targets for personalized interventions. Methods: We performed univariate and multivariate genome-wide association studies (GWAS) on the Nightingale panel of 249 circulating plasma metabolic markers, across 207,836 White British UK Biobank participants (mean age 57.4 years, 53.7% female), with replication conducted across 27,509 UK Biobank participants with different ancestries, and 92,661 Estonian Biobank participants (mean age 50.9 years, 65.7% female). We investigated rare variation through whole exome sequencing gene burden tests, quantified genetic architectures through Gaussian mixture modelling, analysed the causal role of body mass index (BMI) through Mendelian randomization, and performed genome-wide interaction analyses with sex. Results: We discovered 14,837 loci (497 unique), with shared and distinct effects on cardiometabolic traits, with high replication rates across populations. The loci explained over 70% of genetic variance for fatty acids. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. There was strong evidence for causal effects of BMI on cholesterol and amino acid levels. We discovered 31 loci interacting with sex, which mapped to genes involved in cholesterol processing, and to cardiometabolic conditions with sex differences in prevalence. Discussion: The findings offer new insights into the genetic architecture of circulating metabolites, revealing novel loci and plausible sex-specific molecular mechanisms of lipid metabolism. This improved understanding of the molecular biology of metabolism lays a foundation for personalized prevention and treatment strategies.
循环代谢标记物的多效应和性别特异性遗传结构
背景:血浆中的代谢物构成了一系列常见复杂人类疾病的生物特征。绘制遗传结构图并发现对不同代谢物具有多向效应的变异体,可以揭示潜在的机制和个性化干预的潜在靶点:我们对南丁格尔小组的 249 个循环血浆代谢标记物进行了单变量和多变量全基因组关联研究(GWAS),研究对象包括 207836 名英国白种生物库参与者(平均年龄 57.4 岁,53.7% 为女性),并在 27509 名不同血统的英国生物库参与者和 92661 名爱沙尼亚生物库参与者(平均年龄 50.9 岁,65.7% 为女性)中进行了复制。我们通过全外显子组测序基因负荷测试研究了罕见变异,通过高斯混合建模量化了基因结构,通过孟德尔随机化分析了体重指数(BMI)的因果作用,并进行了与性别的全基因组相互作用分析:我们发现了 14837 个位点(497 个唯一位点),这些位点对心脏代谢特征具有共同和独特的影响,在不同人群中的重复率很高。这些基因位点解释了 70% 以上的脂肪酸遗传变异。常见和罕见变异基因测试结果趋同于脂质平衡途径。有强有力的证据表明,体重指数对胆固醇和氨基酸水平有因果效应。我们发现了 31 个与性别相互作用的基因位点,这些位点与胆固醇处理相关基因和发病率存在性别差异的心脏代谢疾病相关:讨论:研究结果为循环代谢物的遗传结构提供了新的见解,揭示了脂质代谢的新基因位点和合理的性别特异性分子机制。对代谢分子生物学的进一步了解为个性化预防和治疗策略奠定了基础。
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