Analysis of shared heritability in common disorders of the brain.
Analysis of shared heritability in common disorders of the brain.
复制标题
DOI：
10.1126/science.aap8757
复制
发表时间：
2018-06-22
期刊：
影响因子：
--
通讯作者：
Murray R
中科院分区：
文献类型：
--
作者：
Brainstorm Consortium;Anttila V;Bulik-Sullivan B;Finucane HK;Walters RK;Bras J;Duncan L;Escott-Price V;Falcone GJ;Gormley P;Malik R;Patsopoulos NA;Ripke S;Wei Z;Yu D;Lee PH;Turley P;Grenier-Boley B;Chouraki V;Kamatani Y;Berr C;Letenneur L;Hannequin D;Amouyel P;Boland A;Deleuze JF;Duron E;Vardarajan BN;Reitz C;Goate AM;Huentelman MJ;Kamboh MI;Larson EB;Rogaeva E;St George-Hyslop P;Hakonarson H;Kukull WA;Farrer LA;Barnes LL;Beach TG;Demirci FY;Head E;Hulette CM;Jicha GA;Kauwe JSK;Kaye JA;Leverenz JB;Levey AI;Lieberman AP;Pankratz VS;Poon WW;Quinn JF;Saykin AJ;Schneider LS;Smith AG;Sonnen JA;Stern RA;Van Deerlin VM;Van Eldik LJ;Harold D;Russo G;Rubinsztein DC;Bayer A;Tsolaki M;Proitsi P;Fox NC;Hampel H;Owen MJ;Mead S;Passmore P;Morgan K;Nöthen MM;Rossor M;Lupton MK;Hoffmann P;Kornhuber J;Lawlor B;McQuillin A;Al-Chalabi A;Bis JC;Ruiz A;Boada M;Seshadri S;Beiser A;Rice K;van der Lee SJ;De Jager PL;Geschwind DH;Riemenschneider M;Riedel-Heller S;Rotter JI;Ransmayr G;Hyman BT;Cruchaga C;Alegret M;Winsvold B;Palta P;Farh KH;Cuenca-Leon E;Furlotte N;Kurth T;Ligthart L;Terwindt GM;Freilinger T;Ran C;Gordon SD;Borck G;Adams HHH;Lehtimäki T;Wedenoja J;Buring JE;Schürks M;Hrafnsdottir M;Hottenga JJ;Penninx B;Artto V;Kaunisto M;Vepsäläinen S;Martin NG;Montgomery GW;Kurki MI;Hämäläinen E;Huang H;Huang J;Sandor C;Webber C;Muller-Myhsok B;Schreiber S;Salomaa V;Loehrer E;Göbel H;Macaya A;Pozo-Rosich P;Hansen T;Werge T;Kaprio J;Metspalu A;Kubisch C;Ferrari MD;Belin AC;van den Maagdenberg AMJM;Zwart JA;Boomsma D;Eriksson N;Olesen J;Chasman DI;Nyholt DR;Avbersek A;Baum L;Berkovic S;Bradfield J;Buono RJ;Catarino CB;Cossette P;De Jonghe P;Depondt C;Dlugos D;Ferraro TN;French J;Hjalgrim H;Jamnadas-Khoda J;Kälviäinen R;Kunz WS;Lerche H;Leu C;Lindhout D;Lo W;Lowenstein D;McCormack M;Møller RS;Molloy A;Ng PW;Oliver K;Privitera M;Radtke R;Ruppert AK;Sander T;Schachter S;Schankin C;Scheffer I;Schoch S;Sisodiya SM;Smith P;Sperling M;Striano P;Surges R;Thomas GN;Visscher F;Whelan CD;Zara F;Heinzen EL;Marson A;Becker F;Stroink H;Zimprich F;Gasser T;Gibbs R;Heutink P;Martinez M;Morris HR;Sharma M;Ryten M;Mok KY;Pulit S;Bevan S;Holliday E;Attia J;Battey T;Boncoraglio G;Thijs V;Chen WM;Mitchell B;Rothwell P;Sharma P;Sudlow C;Vicente A;Markus H;Kourkoulis C;Pera J;Raffeld M;Silliman S;Boraska Perica V;Thornton LM;Huckins LM;William Rayner N;Lewis CM;Gratacos M;Rybakowski F;Keski-Rahkonen A;Raevuori A;Hudson JI;Reichborn-Kjennerud T;Monteleone P;Karwautz A;Mannik K;Baker JH;O'Toole JK;Trace SE;Davis OSP;Helder SG;Ehrlich S;Herpertz-Dahlmann B;Danner UN;van Elburg AA;Clementi M;Forzan M;Docampo E;Lissowska J;Hauser J;Tortorella A;Maj M;Gonidakis F;Tziouvas K;Papezova H;Yilmaz Z;Wagner G;Cohen-Woods S;Herms S;Julià A;Rabionet R;Dick DM;Ripatti S;Andreassen OA;Espeseth T;Lundervold AJ;Steen VM;Pinto D;Scherer SW;Aschauer H;Schosser A;Alfredsson L;Padyukov L;Halmi KA;Mitchell J;Strober M;Bergen AW;Kaye W;Szatkiewicz JP;Cormand B;Ramos-Quiroga JA;Sánchez-Mora C;Ribasés M;Casas M;Hervas A;Arranz MJ;Haavik J;Zayats T;Johansson S;Williams N;Dempfle A;Rothenberger A;Kuntsi J;Oades RD;Banaschewski T;Franke B;Buitelaar JK;Arias Vasquez A;Doyle AE;Reif A;Lesch KP;Freitag C;Rivero O;Palmason H;Romanos M;Langley K;Rietschel M;Witt SH;Dalsgaard S;Børglum AD;Waldman I;Wilmot B;Molly N;Bau CHD;Crosbie J;Schachar R;Loo SK;McGough JJ;Grevet EH;Medland SE;Robinson E;Weiss LA;Bacchelli E;Bailey A;Bal V;Battaglia A;Betancur C;Bolton P;Cantor R;Celestino-Soper P;Dawson G;De Rubeis S;Duque F;Green A;Klauck SM;Leboyer M;Levitt P;Maestrini E;Mane S;De-Luca DM;Parr J;Regan R;Reichenberg A;Sandin S;Vorstman J;Wassink T;Wijsman E;Cook E;Santangelo S;Delorme R;Rogé B;Magalhaes T;Arking D;Schulze TG;Thompson RC;Strohmaier J;Matthews K;Melle I;Morris D;Blackwood D;McIntosh A;Bergen SE;Schalling M;Jamain S;Maaser A;Fischer SB;Reinbold CS;Fullerton JM;Guzman-Parra J;Mayoral F;Schofield PR;Cichon S;Mühleisen TW;Degenhardt F;Schumacher J;Bauer M;Mitchell PB;Gershon ES;Rice J;Potash JB;Zandi PP;Craddock N;Ferrier IN;Alda M;Rouleau GA;Turecki G;Ophoff R;Pato C;Anjorin A;Stahl E;Leber M;Czerski PM;Cruceanu C;Jones IR;Posthuma D;Andlauer TFM;Forstner AJ;Streit F;Baune BT;Air T;Sinnamon G;Wray NR;MacIntyre DJ;Porteous D;Homuth G;Rivera M;Grove J;Middeldorp CM;Hickie I;Pergadia M;Mehta D;Smit JH;Jansen R;de Geus E;Dunn E;Li QS;Nauck M;Schoevers RA;Beekman AT;Knowles JA;Viktorin A;Arnold P;Barr CL;Bedoya-Berrio G;Bienvenu OJ;Brentani H;Burton C;Camarena B;Cappi C;Cath D;Cavallini M;Cusi D;Darrow S;Denys D;Derks EM;Dietrich A;Fernandez T;Figee M;Freimer N;Gerber G;Grados M;Greenberg E;Hanna GL;Hartmann A;Hirschtritt ME;Hoekstra PJ;Huang A;Huyser C;Illmann C;Jenike M;Kuperman S;Leventhal B;Lochner C;Lyon GJ;Macciardi F;Madruga-Garrido M;Malaty IA;Maras A;McGrath L;Miguel EC;Mir P;Nestadt G;Nicolini H;Okun MS;Pakstis A;Paschou P;Piacentini J;Pittenger C;Plessen K;Ramensky V;Ramos EM;Reus V;Richter MA;Riddle MA;Robertson MM;Roessner V;Rosário M;Samuels JF;Sandor P;Stein DJ;Tsetsos F;Van Nieuwerburgh F;Weatherall S;Wendland JR;Wolanczyk T;Worbe Y;Zai G;Goes FS;McLaughlin N;Nestadt PS;Grabe HJ;Depienne C;Konkashbaev A;Lanzagorta N;Valencia-Duarte A;Bramon E;Buccola N;Cahn W;Cairns M;Chong SA;Cohen D;Crespo-Facorro B;Crowley J;Davidson M;DeLisi L;Dinan T;Donohoe G;Drapeau E;Duan J;Haan L;Hougaard D;Karachanak-Yankova S;Khrunin A;Klovins J;Kučinskas V;Lee Chee Keong J;Limborska S;Loughland C;Lönnqvist J;Maher B;Mattheisen M;McDonald C;Murphy KC;Nenadic I;van Os J;Pantelis C;Pato M;Petryshen T;Quested D;Roussos P;Sanders AR;Schall U;Schwab SG;Sim K;So HC;Stögmann E;Subramaniam M;Toncheva D;Waddington J;Walters J;Weiser M;Cheng W;Cloninger R;Curtis D;Gejman PV;Henskens F;Mattingsdal M;Oh SY;Scott R;Webb B;Breen G;Churchhouse C;Bulik CM;Daly M;Dichgans M;Faraone SV;Guerreiro R;Holmans P;Kendler KS;Koeleman B;Mathews CA;Price A;Scharf J;Sklar P;Williams J;Wood NW;Cotsapas C;Palotie A;Smoller JW;Sullivan P;Rosand J;Corvin A;Neale BM;Schott JM;Anney R;Elia J;Grigoroiu-Serbanescu M;Edenberg HJ;Murray R
脑部疾病可表现出相当多的流行病学合并症，并经常有共同症状，引发了关于其病因重叠的争论。我们量化了来自265,218名患者和784,643名对照参与者的全基因组关联研究中的25种脑部疾病的遗传共享，并评估了它们与1,191,588名个体的17种表型的关系。精神疾病具有共同的变异风险，而神经疾病彼此之间以及与精神疾病之间的差异更大。我们还发现了疾病和许多大脑表型之间的显著共享，包括认知测量。此外，我们进行了模拟，以探索统计能力、诊断错误分类和表型异质性如何影响遗传相关性。这些结果强调了常见遗传变异作为脑部疾病风险因素的重要性，以及基于遗传的方法在了解其病因学方面的价值。脑部疾病可能表现出共同的症状和大量的流行病学合并症，引发了关于其病因重叠的争论。然而，对不同发病年龄、严重程度和表现的表型的详细研究提出了相当大的挑战。最近发展的遗传力方法使我们能够准确地测量来自不同个体的两种表型之间的全基因组共同变异风险的相关性，并评估它们之间的联系，或者至少它们的遗传风险在基因组水平上是如何联系的。我们使用了265,218名患者和784,643名对照参与者的全基因组关联数据，以及来自总共1,191,588名个体的17种表型，来量化25种常见脑部疾病遗传风险因素的重叠程度。在过去的一个世纪里，脑部疾病的分类已经发展到反映医学和科学界对临床现象（如行为改变、运动功能丧失或意识改变）的假定根本原因的评估。直接观察到的现象（如栓子、蛋白缠结或异常的电活动模式）通常可以定义和区分神经系统疾病和精神疾病。了解大脑疾病和相关表型的遗传基础和分类差异可能会为寻找其生物学机制提供信息。精神疾病的常见变异风险显着相关，特别是在注意缺陷多动障碍（ADHD），双相情感障碍，重度抑郁症（MDD）和精神分裂症中。相比之下，除了偏头痛与多动症、重度抑郁症和图雷特综合症显著相关外，神经系统疾病与其他疾病和精神疾病之间的区别更明显。我们证明，在一般人群中，人格特质神经质与几乎所有精神疾病和偏头痛显著相关。我们还发现，在普通人群中，疾病与早期生活认知测量（例如，受教育年限和大学学历）之间存在显著的遗传共享，表明与几种精神疾病（例如，神经性厌食症和双相情感障碍）呈正相关，与几种神经表型（例如，阿尔茨海默病和缺血性中风）负相关，尽管后者被认为是由生命后期发生的特定过程导致的。还进行了广泛的模拟，以了解统计能力、诊断错误分类和表型异质性如何影响遗传相关性。许多精神疾病之间高度的遗传相关性进一步证明，至少在遗传水平上，它们目前的临床界限并没有反映出不同的潜在致病过程。这表明，与神经疾病相比，精神疾病具有深刻的相互联系的本质，并强调了改进精神疾病诊断的必要性。基因信息分析可能提供重要的“支架”来支持精神病学的重组，这可能需要整合许多层次的信息。相比之下，我们发现神经系统疾病或神经和精神疾病之间普遍存在共同遗传风险共享的证据有限。我们发现精神疾病和神经疾病都与认知和人格测量有很强的相关性。需要进一步的研究来评估重叠的基因对精神病理学的贡献是否会影响治疗的选择。最终，这些发展可能会为减少异质性和改善精神疾病的诊断和治疗铺平道路。脑疾病与定量表型之间遗传风险相关性的分节。脑部疾病的遗传分析指出，精神疾病之间普遍存在遗传风险共享。这些相关性在神经系统疾病中基本上不存在，但在两组中都存在与神经认知定量表型相关的相关性。只显示出显著的相关性。线的颜色和坚固度分别表示相关性的方向和大小。
Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology. Brain disorders may exhibit shared symptoms and substantial epidemio-logical comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyper-activity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply intercon nected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders. Subsection of genetic risk correlations among brain disorders and quantitative phenotypes. Heritability analysis of brain disorders points to pervasive sharing of genetic risk among psychiatric disorders. These correlations are largely absent among neurological disorders but are present for both groups in relation to neurocognitive quantitative phenotypes. Only significant correlations shown. Line color and solidity indicate direction and magnitude of correlation, respectively.
登录
查看更多内容
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
11
作者：
通讯作者：
--
影响因子：
64.8
作者：
Deary, Ian J.;Yang, Jian;Visscher, Peter M.
通讯作者：
Visscher, Peter M.
影响因子：
11
作者：
Cristino, A. S.;Williams, S. M.;Claudianos, C.
通讯作者：
Claudianos, C.
影响因子：
--
作者：
Kendler, Kenneth S.;Gatz, Margaret;Pedersen, Nancy L.
通讯作者：
Pedersen, Nancy L.