Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease

Stacy Steinberg; Hreinn Stefansson; Thorlakur Jonsson; Hrefna Johannsdottir; Andres Ingason; Hannes Helgason; Patrick Sulem; Olafur Th Magnusson; Sigurjon A Gudjonsson; Unnur Unnsteinsdottir; Augustine Kong; Seppo Helisalmi; Hilkka Soininen; James J Lah; DemGene; Dag Aarsland; Tormod Fladby; Ingun D Ulstein; Srdjan Djurovic; Sigrid B Sando; Linda R White; Gun-Peggy Knudsen; Lars T Westlye; Geir Selbæk; Ina Giegling; Harald Hampel; Mikko Hiltunen; Allan I Levey; Ole A Andreassen; Dan Rujescu; Palmi V Jonsson; Sigurbjorn Bjornsson; Jon Snaedal; Kari Stefansson

doi:10.1038/ng.3246

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease

Nat Genet. 2015 May;47(5):445-7. doi: 10.1038/ng.3246. Epub 2015 Mar 25.

Authors

Stacy Steinberg¹, Hreinn Stefansson¹, Thorlakur Jonsson¹, Hrefna Johannsdottir¹, Andres Ingason¹, Hannes Helgason¹, Patrick Sulem¹, Olafur Th Magnusson¹, Sigurjon A Gudjonsson¹, Unnur Unnsteinsdottir¹, Augustine Kong¹, Seppo Helisalmi², Hilkka Soininen², James J Lah³; DemGene; Dag Aarsland¹², Tormod Fladby¹³, Ingun D Ulstein¹⁴, Srdjan Djurovic¹⁵, Sigrid B Sando¹⁶, Linda R White¹⁶, Gun-Peggy Knudsen¹⁷, Lars T Westlye¹⁸, Geir Selbæk⁷, Ina Giegling¹⁹, Harald Hampel²⁰, Mikko Hiltunen²¹, Allan I Levey³, Ole A Andreassen²², Dan Rujescu¹⁹, Palmi V Jonsson²³, Sigurbjorn Bjornsson²⁴, Jon Snaedal²⁴, Kari Stefansson²⁵

Collaborators

DemGene:
Ina Selseth Almdahl⁴, Fred Andersen⁵, Nenad Bogdanovic⁶, Anne Brækhus⁶, Knut Engedal⁷, Arvid Rongve⁸, Ingvild Saltvedt⁹, Eystein Stordal¹⁰, Aree Witoelar¹¹

Affiliations

¹ deCODE Genetics, Reykjavik, Iceland.
² 1] Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland. [2] NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
³ School of Medicine, Emory University, Atlanta, Georgia, USA.
⁴ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
⁵ Department of Community Medicine, University of Tromsø, Tromsø, Norway.
⁶ Geriatric Department, University Hospital Oslo and University of Oslo, Oslo, Norway.
⁷ Ageing and Health, Norwegian Centre for Research, Education and Service Development, Vestfold Hospital Trust, Tønsberg, Norway.
⁸ 1] Division of Mental Health, Helse Fonna, Haugesund, Norway. [2] Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁹ Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ 1] Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. [2] Department of Psychiatry, Namsos Hospital, Namsos, Norway.
¹¹ 1] Institute of Clinical Medicine, University of Oslo, Oslo, Norway. [2] NORMENT-K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹² 1] Alzheimer's Disease Research Centre, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. [2] Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway. [3] Institute of Clinical Medicine, Division of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway.
¹³ 1] Institute of Clinical Medicine, Division of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway. [2] Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
¹⁴ 1] Department of Psychiatry of Old Age, Oslo University Hospital, Oslo, Norway. [2] Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁵ 1] Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. [2] NORMENT-K.G. Jebsen Centre, Department of Clinical Science, University of Bergen, Bergen, Norway.
¹⁶ 1] Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. [2] Department of Neurology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
¹⁷ Division of Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
¹⁸ 1] NORMENT-K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. [2] Department of Psychology, University of Oslo, Oslo, Norway.
¹⁹ Department of Psychiatry, University of Halle, Halle, Germany.
²⁰ Sorbonne Universités, Université Pierre et Marie Curie, Département de Neurologie, Hôpital Pitié Salpêtrière, Paris, France.
²¹ 1] Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland. [2] NeuroCenter, Kuopio University Hospital, Kuopio, Finland. [3] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
²² 1] NORMENT-K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. [2] NORMENT-K.G. Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²³ 1] Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [2] Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
²⁴ Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
²⁵ 1] deCODE Genetics, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

PMID: 25807283
DOI: 10.1038/ng.3246

Abstract

We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10(-15)).

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

ATP-Binding Cassette Transporters / genetics*
Alzheimer Disease / genetics*
Case-Control Studies
Genetic Association Studies
Genetic Predisposition to Disease
Haplotypes
Humans
Mutation
Risk
Sequence Analysis, DNA

Substances

ABCA7 protein, human
ATP-Binding Cassette Transporters