Polygenic Liability to Depression Is Associated With Multiple Medical Conditions in the Electronic Health Record: Phenome-wide Association Study of 46,782 Individuals
Polygenic Liability to Depression Is Associated With Multiple Medical Conditions in the Electronic Health Record: Phenome-wide Association Study of 46,782 Individuals
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DOI：
10.1016/j.biopsych.2022.06.004
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发表时间：
2022-11-14
影响因子：
10.6
通讯作者：
Richmond-Rakerd, Leah S.
中科院分区：
文献类型：
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作者：
Fang, Yu;Fritsche, Lars G.;Richmond-Rakerd, Leah S.
背景：严重抑郁障碍(MDD)是疾病相关残疾的主要原因，大部分增加的负担是由于精神和内科共病造成的。这种共病在一定程度上反映了各种情况下共同的遗传影响。将分子遗传学工具与健康记录相结合，能够对广泛的生理和临床表型进行关联测试。然而，标准的表现组范围的关联研究分析了与个体遗传变异的关联。对于像MDD这样的多基因特征，对遗传风险的综合测量可能会更好地洞察整个临床现象的相关性。方法：我们在一项来自密歇根基因组学倡议的46,782名无关的欧洲血统参与者的全基因组关联研究中，测试了MDD的全基因组多基因风险分数与医学和精神特征之间的关联。结果：MDD多基因风险分数与来自15个医学和精神疾病类别的211个性状在表型范围的显著阈值下相关。排除抑郁症患者后，继续观察到与呼吸、消化、神经和泌尿生殖系统疾病、肿瘤和精神障碍的相关性。在解释了抑郁症和其他精神特征之间的遗传重叠后，与烟草使用障碍、呼吸状况和泌尿生殖系统状况的关联仍然存在。首次诊断时间的时间分析表明，抑郁不成比例地先于慢性疼痛和与物质相关的疾病，而哮喘不成比例地先于抑郁。结论：本研究结果可以揭示抑郁与精神和全身疾病之间的生物学联系。尽管MDD多基因风险评分目前不能在个体水平上准确地预测健康结果，但随着抑郁症的分子遗传学发现的增加，这些工具可能会增强对医疗和精神疾病的风险预测。
BACKGROUND: Major depressive disorder (MDD) is a leading cause of disease-associated disability, with much of the increased burden due to psychiatric and medical comorbidity. This comorbidity partly reflects common genetic influences across conditions. Integrating molecular-genetic tools with health records enables tests of association with the broad range of physiological and clinical phenotypes. However, standard phenome-wide association studies analyze associations with individual genetic variants. For polygenic traits such as MDD, aggregate measures of genetic risk may yield greater insight into associations across the clinical phenome.METHODS: We tested for associations between a genome-wide polygenic risk score for MDD and medical and psychiatric traits in a phenome-wide association study of 46,782 unrelated, European-ancestry participants from the Michigan Genomics Initiative.RESULTS: The MDD polygenic risk score was associated with 211 traits from 15 medical and psychiatric disease categories at the phenome-wide significance threshold. After excluding patients with depression, continued associations were observed with respiratory, digestive, neurological, and genitourinary conditions; neoplasms; and mental disorders. Associations with tobacco use disorder, respiratory conditions, and genitourinary conditions persisted after accounting for genetic overlap between depression and other psychiatric traits. Temporal analyses of time-at-first-diagnosis indicated that depression disproportionately preceded chronic pain and substancerelated disorders, while asthma disproportionately preceded depression.CONCLUSIONS: The present results can inform the biological links between depression and both mental and systemic diseases. Although MDD polygenic risk scores cannot currently forecast health outcomes with precision at the individual level, as molecular-genetic discoveries for depression increase, these tools may augment risk prediction for medical and psychiatric conditions.