Genetic architecture of subcortical brain structures in 38,851 individuals

被引：180

作者：

Satizabal, Claudia L. ^{[1
,2
,3
,4
]}

Adams, Hieab H. H. ^{[5
,6
,7
]}

Hibar, Derrek P. ^{[8
]}

White, Charles C. ^{[9
,10
]}

Knol, Maria J. ^{[5
]}

Stein, Jason L. ^{[8
,11
,12
]}

Scholz, Markus ^{[13
,14
]}

Sargurupremraj, Muralidharan ^{[15
]}

Jahanshad, Neda ^{[8
]}

Roshchupkin, Gennady, V ^{[5
,6
,16
]}

Smith, Albert, V ^{[17
,18
,19
]}

Bis, Joshua C. ^{[20
]}

Jian, Xueqiu ^{[21
]}

Luciano, Michelle ^{[22
]}

Hofer, Edith ^{[23
,24
]}

Teumer, Alexander ^{[25
]}

van der Lee, Sven J. ^{[5
]}

Yang, Jingyun ^{[26
,27
]}

Yanek, Lisa R. ^{[28
]}

Lee, Tom, V ^{[29
]}

Li, Shuo ^{[30
]}

Hu, Yanhui ^{[31
]}

Koh, Jia Yu ^{[32
]}

Eicher, John D. ^{[33
]}

Desrivieres, Sylvane ^{[34
]}

Arias-Vasquez, Alejandro ^{[35
,36
,37
,38
]}

Chauhan, Ganesh ^{[15
,39
]}

Athanasiu, Lavinia ^{[40
,41
]}

Rentera, Miguel E. ^{[42
]}

Kim, Sungeun ^{[43
,44
,45
]}

Hoehn, David ^{[46
]}

Armstrong, Nicola J. ^{[47
]}

Chen, Qiang ^{[48
]}

Holmes, Avram J. ^{[49
,50
]}

den Braber, Anouk ^{[51
,52
,53
,54
]}

Kloszewska, Iwona ^{[55
]}

Andersson, Micael ^{[56
,57
]}

Espeseth, Thomas ^{[40
,58
]}

Grimm, Oliver ^{[59
]}

Abramovic, Lucija ^{[60
]}

Alhusaini, Saud ^{[61
,62
]}

Milaneschi, Yuri ^{[63
]}

Papmeyer, Martina ^{[64
,65
]}

Axelsson, Tomas ^{[66
]}

Ehrlich, Stefan ^{[50
,67
,68
]}

Roiz-Santianez, Roberto ^{[69
,70
,71
]}

Kraemer, Bernd ^{[72
]}

Haberg, Asta K. ^{[73
,74
]}

Jones, Hannah J. ^{[75
,76
,77
,78
]}

Pike, G. Bruce ^{[79
,80
]}

机构：

[1] UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX 78229 USA

[2] UT Hlth San Antonio, Dept Populat Hlth Sci, San Antonio, TX 78229 USA

[3] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA

[4] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[5] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[6] Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands

[7] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands

[8] Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA

[9] Broad Inst, Cell Circuits Program, Cambridge, MA USA

[10] Columbia Univ, Dept Neurol, Med Ctr, Ctr Translat & Computat Neuroimmunol, New York, NY USA

[11] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[12] Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC 27515 USA

[13] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[14] Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany

[15] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, Team Vintage, INSERM,UMR 1219, Bordeaux, France

[16] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands

[17] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[18] Univ Iceland, Fac Med, Reykjavik, Iceland

[19] Iceland Heart Assoc, Kopavogur, Iceland

[20] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[21] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[22] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland

[23] Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria

[24] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria

[25] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[26] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[27] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA

[28] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA

[29] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA

[30] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[31] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[32] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore

[33] NHLBI, Div Intramural Res, Populat Sci Branch, Framingham, MA USA

[34] Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London, England

[35] Radboud Univ Nijmegen, Dept Cognit Neurosci, Med Ctr, Nijmegen, Netherlands

[36] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands

[37] Radboud Univ Nijmegen, Dept Psychiat, Med Ctr, Nijmegen, Netherlands

[38] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands

[39] Indian Inst Sci, Ctr Brain Res, Bangalore, Karnataka, India

[40] Oslo Univ Hosp, Div Mental Hlth & Addict, CoE NORMENT, Oslo, Norway

[41] Univ Oslo, Inst Clin Med, CoE NORMENT, Oslo, Norway

[42] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia

[43] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA

[44] Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA

[45] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA

[46] Max Planck Inst Psychiat, Munich, Germany

[47] Murdoch Univ, Math & Stat, Perth, WA, Australia

[48] Lieber Inst Brain Dev, Baltimore, MD USA

[49] Yale Univ, Dept Psychol, New Haven, CT USA

[50] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

来源：

NATURE GENETICS | 2019年 / 51卷 / 11期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; LD SCORE REGRESSION; BASAL GANGLIA; ALKALINE-PHOSPHATASE; ALZHEIMERS-DISEASE; PLASMA-PROTEIN; RISK LOCI; DROSOPHILA; METAANALYSIS; EXPRESSION;

D O I：

10.1038/s41588-019-0511-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

引用

页码：1624 / +

页数：16

共 101 条

[1] Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-β and is overexpressed in dystrophic neurites in Alzheimer's brain [J].

Abad, Maria A. ;

Enguita, Marta ;

DeGregorio-Rocasolano, Nuria ;

Ferrer, Isidre ;

Trullas, Ramon .

JOURNAL OF NEUROSCIENCE, 2006, 26 (49) :12735-12747

[2] Novel genetic loci underlying human intracranial volume identified through genome-wide association [J].

Adams, Hieab H. H. ;

Hibar, Derrek P. ;

Chouraki, Vincent ;

Stein, Jason L. ;

Nyquist, Paul A. ;

Renteria, Miguel E. ;

Trompet, Stella ;

Arias-Vasquez, Alejandro ;

Seshadri, Sudha ;

Desrivieres, Sylvane ;

Beecham, Ashley H. ;

Jahanshad, Neda ;

Wittfeld, Katharine ;

Van der Lee, Sven J. ;

Abramovic, Lucija ;

Alhusaini, Saud ;

Amin, Najaf ;

Andersson, Micael ;

Arfanakis, Konstantinos ;

Aribisala, Benjamin S. ;

Armstrong, Nicola J. ;

Athanasiu, Lavinia ;

Axelsson, Tomas ;

Beiser, Alexa ;

Bernard, Manon ;

Bis, Joshua C. ;

Blanken, Laura M. E. ;

Blanton, Susan H. ;

Bohlken, Marc M. ;

Boks, Marco P. ;

Bralten, Janita ;

Brickman, Adam M. ;

Carmichael, Owen ;

Chakravarty, M. Mallar ;

Chauhan, Ganesh ;

Chen, Qiang ;

Ching, Christopher R. K. ;

Cuellar-Partida, Gabriel ;

Den Braber, Anouk ;

Doan, Nhat Trung ;

Ehrlich, Stefan ;

Filippi, Irina ;

Ge, Tian ;

Giddaluru, Sudheer ;

Goldman, Aaron L. ;

Gottesman, Rebecca F. ;

Greven, Corina U. ;

Grimm, Oliver ;

Griswold, Michael E. ;

Guadalupe, Tulio .

NATURE NEUROSCIENCE, 2016, 19 (12) :1569-1582

[3] PARALLEL ORGANIZATION OF FUNCTIONALLY SEGREGATED CIRCUITS LINKING BASAL GANGLIA AND CORTEX [J].

ALEXANDER, GE ;

DELONG, MR ;

STRICK, PL .

ANNUAL REVIEW OF NEUROSCIENCE, 1986, 9 :357-381

[4] Multipoint quantitative-trait linkage analysis in general pedigrees [J].

Almasy, L ;

Blangero, J .

AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (05) :1198-1211

[5] Memory complaints are related to Alzheimer disease pathology in older persons [J].

Barnes, L. L. ;

Schneider, J. A. ;

Boyle, P. A. ;

Bienias, J. L. ;

Bennett, D. A. .

NEUROLOGY, 2006, 67 (09) :1581-1585

[6] Pregnancy-associated plasma protein a as a marker of acute coronary syndromes [J].

Bayes-Genis, A ;

Conover, CA ;

Overgaard, MT ;

Bailey, KR ;

Christiansen, M ;

Holmes, DR ;

Virmani, R ;

Oxvig, C ;

Schwartz, RS .

NEW ENGLAND JOURNAL OF MEDICINE, 2001, 345 (14) :1022-1029

[7] Building a pipeline to discover and validate novel therapeutic targets and lead compounds for Alzheimer's disease [J].

Bennett, David A. ;

Yu, Lei ;

De Jager, Philip L. .

BIOCHEMICAL PHARMACOLOGY, 2014, 88 (04) :617-630

[8]

Bennett DA, 2012, CURR ALZHEIMER RES, V9, P646

[9]

Bennett DA, 2012, CURR ALZHEIMER RES, V9, P628

[10] Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation [J].

Bis, Joshua C. ;

Jian, Xueqiu ;

Kunkle, Brian W. ;

Chen, Yuning ;

Hamilton-Nelson, Kara L. ;

Bush, William S. ;

Salerno, William J. ;

Lancour, Daniel ;

Ma, Yiyi ;

Renton, Alan E. ;

Marcora, Edoardo ;

Farrell, John J. ;

Zhao, Yi ;

Qu, Liming ;

Ahmad, Shahzad ;

Amin, Najaf ;

Amouyel, Philippe ;

Beecham, Gary W. ;

Below, Jennifer E. ;

Campion, Dominique ;

Charbonnier, Camille ;

Chung, Jaeyoon ;

Crane, Paul K. ;

Cruchaga, Carlos ;

Cupples, L. Adrienne ;

Dartigues, Jean-Francois ;

Debette, Stephanie ;

Deleuze, Jean-Francois ;

Fulton, Lucinda ;

Gabriel, Stacey B. ;

Genin, Emmanuelle ;

Gibbs, Richard A. ;

Goate, Alison ;

Grenier-Boley, Benjamin ;

Gupta, Namrata ;

Haines, Jonathan L. ;

Havulinna, Aki S. ;

Helisalmi, Seppo ;

Hiltunen, Mikko ;

Howrigan, Daniel P. ;

Ikram, M. Arfan ;

Kaprio, Jaakko ;

Konrad, Jan ;

Kuzma, Amanda ;

Lander, Eric S. ;

Lathrop, Mark ;

Lehtimaki, Terho ;

Lin, Honghuang ;

Mattila, Kari ;

Mayeux, Richard .

MOLECULAR PSYCHIATRY, 2020, 25 (08) :1859-1875

← 1 2 3 4 5 6 7 8 9 10 →