Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence,JAMA Psychiatry

当前位置： X-MOL 学术 › JAMA Psychiatry › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence
JAMA Psychiatry ( IF 25.8 ) Pub Date : 2017-11-01 , DOI: 10.1001/jamapsychiatry.2017.2269
Allan M. Andersen ₁ , Robert H. Pietrzak ₂ , Henry R. Kranzler ₃ , Li Ma ₄ , Hang Zhou ₅ , Xiaoming Liu ₆ , John Kramer ₁ , Samuel Kuperman ₁ , Howard J. Edenberg ₇ , John I. Nurnberger ₈ , John P. Rice ₉ , Jay A. Tischfield ₁₀ , Alison Goate ₁₁ , Tatiana M. Foroud ₁₂ , Jacquelyn L. Meyers ₁₃ , Bernice Porjesz ₁₃ , Danielle M. Dick ₁₄ , Victor Hesselbrock ₁₅ , Eric Boerwinkle ₆ , Steven M. Southwick ₂ , John H. Krystal ₂ , Myrna M. Weissman ₁₆ , Douglas F. Levinson ₁₇ , James B. Potash ₁₈ , Joel Gelernter ₂ , Shizhong Han ₁₉

Affiliation

Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City
US Department of Veterans Affairs (VA) National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven3Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia5Mental Illness, Research, Education and Clinical Center of Veterans Integrated Service Network 4, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania
Department of Animal and Avian Sciences, University of Maryland, College Park
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
Human Genetics Center, University of Texas Health Science Center at Houston
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis
Department of Psychiatry, Indiana University School of Medicine, Indianapolis
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis
Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn
Departments of Psychology and Human and Molecular Genetics, Virginia Commonwealth University, Richmond
Department of Psychiatry, University of Connecticut School of Medicine, Farmington
Division of Epidemiology, New York State Psychiatric Institute, New York18Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, New York19Columbia University, Mailman School of Public Health, New York, New York
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California
Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City21Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City22now with the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City22now with the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland

Importance Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive.

Objective To examine whether AD and MDD overlap genetically, using a polygenic score approach.

Design, Settings, and Participants Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set.

Main Outcomes and Measures Association between MDD PRS and AD.

Results Participants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10⁻⁶, R² = 0.026; SAGE: best P = .001, R² = 0.01; Yale-Penn: best P = .035, R² = 0.0018; and NHRVS: best P = .004, R² = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10⁻⁹). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10⁻⁶, R² = 0.023; Yale-Penn: best P = .08, R² = 0.0013; and NHRVS: best P = .006, R² = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007).

Conclusions and Relevance These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.

中文翻译：

主要抑郁症和酒精依赖风险的多基因评分

重要性 重度抑郁症（MDD）和酒精依赖（AD）是具有重大公共卫生负担的可遗传性疾病，通常是合并症。已经在家庭，双胞胎和收养研究中寻求了影响MDD和AD并发的常见遗传因素，迄今为止的结果令人鼓舞，但尚无定论。

目的使用多基因评分方法检查AD和MDD是否在基因上重叠。

设计，地点和参与者的 关联分析在来自4个独立的全基因组关联研究（GWAS）数据集的欧洲血统样本中进行MDD多基因风险评分（PRS）和AD病例对照状态之间的比较：酒精中毒遗传学的合作研究（COGA）；对成瘾，遗传学和环境的研究（SAGE）；Yale-Penn物质依赖的遗传研究；以及国家退伍军人健康与抵御能力研究（NHRVS）。从MDD的荟萃分析的结果（9240名MDD患者和9519个控制）从精神病基因组协会被应用于计算PRS在阈值从P <0.05到P 在每个AD GWAS数据集≤0.99。

MDD PRS和AD之间的主要成果和措施关联。

结果分析的参与者包括788例（548 [69.5％]男性；平均[SD]年龄，38.2 [10.8]岁）和522例对照（151 [28.9。％]男性； [SD]年龄，43.9 [11.6]岁） COGA；从SAGE获得了631例病例（333 [52.8％]男性；年龄[SD]，35.0 [7.7]岁）和756例对照（260 [34.4％]男性；年龄[SD] 36.1 [7.7]岁）；Yale-Penn的2135例病例（1375 [64.4％]男性；年龄[SD]，39.4 [11.5]岁）和350例对照（126 [36.0％]男性；年龄[SD]，43.5 [13.9]岁）；来自NHRVS的317例（295例[93.1％]男性；年龄[SD]，59.1 [13.1]岁）和1719例对照（1545例[89.9％]男性；年龄[SD]，64.5 [13.3]岁）。在所有样本中，较高的MDD PRS与AD风险显着增加相关（COGA：最佳P = 1.7×10 ^-6，R ² = 0.026； SAGE：最佳P = .001，R ² = 0.01；耶鲁-彭（Yale-Penn）：最佳P = .035，R ² = 0.0018；NHRVS：最佳P = .004，R ² = 0.0074），在对4个样本进行荟萃分析后，有更强的关联证据（最佳P = 3.3×10 ^-9）。在3个AD GWAS数据集中针对MDD状态进行调整的分析中，观察到相似的关联模式（COGA：最佳P = 7.6×10 ^-6，R ² = 0.023； Yale-Penn：最佳P = 0.08，R ² = 0.0013 ；和NHRVS：最佳P = .006 ，R ² = 0.0072）。在没有合并MDD-AD病例的情况下，使用MDD GWAS数据集重新计算MDD PRS之后，在3个没有MDD病例的GWAS AD样本的荟萃分析中，观察到了MDD PRS和AD之间关联的重要证据（最佳P = .007）。