Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk

被引：1423

作者：

Jansen, Iris E. ^{[1
,2
]}

Savage, Jeanne E. ^{[1
]}

Watanabe, Kyoko ^{[1
]}

Bryois, Julien ^{[3
]}

Williams, Dylan M. ^{[3
]}

Steinberg, Stacy ^{[4
]}

Sealock, Julia ^{[5
]}

Karlsson, Ida K. ^{[3
,6
]}

Hagg, Sara ^{[3
]}

Athanasiu, Lavinia ^{[7
,8
]}

Voyle, Nicola ^{[9
]}

Proitsi, Petroula ^{[9
]}

Witoelar, Aree ^{[7
,10
]}

Stringer, Sven ^{[1
]}

Aarsland, Dag ^{[9
,11
]}

Almdahl, Ina S. ^{[12
,13
,14
]}

Andersen, Fred ^{[15
]}

Bergh, Sverre ^{[16
,17
]}

Bettella, Francesco ^{[7
,10
]}

Bjornsson, Sigurbjorn ^{[18
]}

Braekhus, Anne ^{[16
,19
]}

Brathen, Geir ^{[20
,21
]}

de Leeuw, Christiaan ^{[1
]}

Desikan, Rahul S. ^{[22
]}

Djurovic, Srdjan ^{[7
,23
]}

Dumitrescu, Logan ^{[24
,25
]}

Fladby, Tormod ^{[12
,13
]}

Hohman, Timothy J. ^{[24
,25
]}

Jonsson, Palmi, V ^{[18
,26
]}

Kiddle, Steven J. ^{[27
]}

Rongve, Arvid ^{[28
,29
]}

Saltvedt, Ingvild ^{[20
,30
]}

Sando, Sigrid B. ^{[20
,21
]}

Selbaek, Geir ^{[16
,31
]}

Shoai, Maryam ^{[32
]}

Skene, Nathan G. ^{[33
,34
]}

Snaedal, Jon ^{[18
]}

Stordal, Eystein ^{[35
,36
]}

Ulstein, Ingun D. ^{[37
]}

Wang, Yunpeng ^{[7
,10
]}

White, Linda R. ^{[20
,21
]}

Hardy, John ^{[32
]}

Hjerling-Leffler, Jens ^{[33
]}

Sullivan, Patrick F. ^{[3
,38
,39
]}

van der Flier, Wiesje M. ^{[2
]}

Dobson, Richard ^{[9
,40
,41
,42
,43
]}

Davis, Lea K. ^{[25
,44
]}

Stefansson, Hreinn ^{[4
]}

Stefansson, Kari ^{[4
]}

Pedersen, Nancy L. ^{[3
]}

机构：

[1] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, Amsterdam Neurosci, Amsterdam, Netherlands

[2] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands

[3] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[4] deCODE Genet Amgen, Reykjavik, Iceland

[5] Vanderbilt Univ, Interdisciplinary Grad Program, 221 Kirkland Hall, Nashville, TN 37235 USA

[6] Jonkoping Univ, Sch Hlth & Welf, Inst Gerontol & Aging Res Network Jonkoping ARN J, Jonkoping, Sweden

[7] Univ Oslo, KG Jebsen Ctr Psychosis Res, Inst Clin Med, NORMENT, Oslo, Norway

[8] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[9] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England

[10] Univ Oslo, Inst Clin Med, Oslo, Norway

[11] Stavanger Univ Hosp, Ctr Age Related Dis, Stavanger, Norway

[12] Akershus Univ Hosp, Dept Neurol, Lorenskog, Norway

[13] Univ Oslo, AHUS Campus, Oslo, Norway

[14] Oslo Univ Hosp, Dept Psychiat Old Age, Oslo, Norway

[15] Univ Tromso, Dept Community Med, Tromso, Norway

[16] Vestfold Hosp Trust, Norwegian Natl Advisory Unit Ageing & Hlth, Tonsberg, Norway

[17] Innlandet Hosp Trust, Ctr Old Age Psychiat Res, Ottestad, Norway

[18] Landspitali Univ Hosp, Dept Geriatr Med, Reykjavik, Iceland

[19] Oslo Univ Hosp, Geriatr Dept, Oslo, Norway

[20] Norwegian Univ Sci & Technol, Dept Neuromed & Movement Sci, Trondheim, Norway

[21] Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Neurol, Trondheim, Norway

[22] Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA

[23] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[24] Vanderbilt Univ, Med Ctr, Dept Neurol, Vanderbilt Memory & Alzheimers Ctr, Nashville, TN USA

[25] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

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

[27] Univ Cambridge, Cambridge Inst Publ Hlth, MRC Biostat Unit, Cambridge, England

[28] Helse Fonna, Dept Res & Innovat, Haugesund, Norway

[29] Univ Bergen, Dept Clin Med, Bergen, Norway

[30] Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Geriatr, Trondheim, Norway

[31] Univ Oslo, Inst Hlth & Soc, Oslo, Norway

[32] UCL, Dept Neurodegenerat Disorders, Inst Neurol, London, England

[33] Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Stockholm, Sweden

[34] UCL, Inst Neurol, Dept Neuromuscular Dis, London, England

[35] Namsos Hosp, Dept Psychiat, Namsos, Norway

[36] Norwegian Univ Sci & Technol, Dept Mental Hlth, Trondheim, Norway

[37] Oslo Univ Hosp, Geriatr Dept, Memory Clin, Oslo, Norway

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

[39] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA

[40] South London & Maudsley NHS Fdn Trust, NIHR Biomed Res Ctr, London, England

[41] Kings Coll London, London, England

[42] UCL, Inst Hlth Informat Res, London, England

[43] UCL, Hlth Data Res UK London, London, England

[44] Vanderbilt Univ, Med Ctr, Dept Med, Div Genet Med, Nashville, TN USA

[45] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[46] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[47] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany

[48] Vrije Univ Amsterdam, Dept Clin Genet, Med Ctr, Amsterdam, Netherlands

来源：

NATURE GENETICS | 2019年 / 51卷 / 03期

关键词：

POLYGENIC RISK; MISSENSE MUTATIONS; COGNITIVE RESERVE; GENE-EXPRESSION; VARIANTS; ASSOCIATION; RARE; ANNOTATION; DISCOVERY; DEMENTIA;

D O I：

10.1038/s41588-018-0311-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (r(g) = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

引用

页码：404 / +

页数：13

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