Shared genetic loci between depression and cardiometabolic traits

Abstract

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.

New insights from the last decade of research in psychiatric genetics: discoveries, challenges and clinical implications

“…Genetic influences of psychiatric disorders are shown to overlap with a wide range of brain-related and somatic human traits and disorders, including cognitive traits 86,[177][178][179][180] , neurological disorders [181][182][183][184][185][186] , substance use [187][188][189] , and cardiovascular disease and risk factors [190][191][192][193] . Among the many cross-trait genetic associations, it is important to emphasize that psychiatric disorders are also genetically linked to positive traits, which we believe is an important message to communicate to patients and the public.…”

Clinical and Genetic Aspects of Depression Comorbid Coronary Heart Disease

“…Поиск перекрывающихся регионов генома для депрессии и ИБС выявил 675 общих генов [76]. В другом исследовании обнаружено шесть регионов, общих для депрессии и ИБС, при этом варианты, ассоциированные с риском депрессии, составляли риск не только ИБС, но и повышенного содержания триглицеридов, липопротеина низкой плотности и С-реактивного белка [77].…”

“…Что касается конкретных генов риска развития депрессии и ИБС, то в их число могут входить гены, связанные с различными важными для обеспечения жизнедеятельности организма системами. Так, по данным метаанализа [77], выявлено 24 гена-кандидата, в том числе гены, участвующие в различных метаболических путях: в передаче сигналов кортикотропин-высвобождающего гормона, АМП-активированной протеинкиназы как ведущего регулятора энергетического гомеостаза; цАМФ-опосредованного и связанного с G-белками рецептора, а также гены моноаминергических и адренергической систем, фолатного цикла, нейротрофических и транскрипционных факторов, циркадианных ритмов и др. Список может быть пополнен за счет ключевых генов-кандидатов, ассоциированных с процессом воспаления и обменом серотонина, а также эндотелиальной дисфункцией, которые являются общими патогенетическими звеньями как депрессии, так и ИБС.…”

Causal relationships between birth weight, childhood obesity and age at menarche: A two‐sample Mendelian randomization analysis

“…Moreover, a previous study has shown that MR analysis using summary statistics has similar efficiency as using individual‐level data 30 . In the present study, we utilized single‐nucleotide polymorphisms (SNPs) strongly associated with BW/CBMI as IVs and performed two‐sample MR analyses using the effect of IVs on the exposures and outcomes from large GWASs 15,31,32 . The summary‐level data were analysed to obtain quantitative estimates of the causal effects of BW and CBMI on the AAM to investigate the potential role of BW and CBMI on AAM.…”