Department of Economics and Business Economics

Genetic Overlap Between Alzheimer's Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

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DOI

  • Ole Kristian Drange, Trondheim Reg & Univ Hosp, Norwegian University of Science & Technology (NTNU), St Olavs Hosp, Dept Ostmarka, Div Mental Hlth Care
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  • Olav Bjerkehagen Smeland, Oslo Univ Hosp, University of Oslo, Norwegian Ctr Mental Disorders Res, Div Mental Hlth & Addict
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  • Alexey A. Shadrin, Univ Oslo, University of Oslo, Norwegian Ctr Mental Disorders Res, KG Jebsen Ctr Psychosis Res, Inst Clin Med
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  • Per Ivar Finseth, Trondheim Reg & Univ Hosp, Norwegian University of Science & Technology (NTNU), Dept Broset, Div Mental Hlth Care, St Olavs Hosp
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  • Aree Witoelar, Oslo Univ Hosp, University of Oslo, Norwegian Ctr Mental Disorders Res, Div Mental Hlth & Addict
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  • Oleksandr Frei, Univ Oslo, University of Oslo, Norwegian Ctr Mental Disorders Res, KG Jebsen Ctr Psychosis Res, Inst Clin Med
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  • Psychiat Genomics Consortium Bipol
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  • Yunpeng Wang, Oslo Univ Hosp, University of Oslo, Norwegian Ctr Mental Disorders Res, Div Mental Hlth & Addict
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  • Sahar Hassani, Oslo Univ Hosp, University of Oslo, Dept Med Genet, Norwegian Radium Hosp, Res Grp Inherited Canc
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  • Srdjan Djurovic, Univ Bergen, University of Bergen, Norwegian Ctr Mental Disorders Res, KG Jebsen Ctr Psychosis Res, Dept Clin Sci
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  • Anders M. Dale, Univ Calif San Diego, University of California System, University of California San Diego, Dept Psychiat
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  • Ole A. Andreassen, Oslo Univ Hosp, University of Oslo, Norwegian Ctr Mental Disorders Res, Div Mental Hlth & Addict

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.

Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.

Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).

Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

Original languageEnglish
Article number220
JournalFrontiers in Neuroscience
Volume13
Number of pages11
ISSN1662-453X
DOIs
Publication statusPublished - 13 Mar 2019

    Research areas

  • Alzheimer's disease, bipolar disorder, GWAS, pleiotropy, cognitive symptoms, affective symptoms, MARK2, VAC14, GENOME-WIDE ASSOCIATION, RISK VARIANT, PHOSPHATIDYLINOSITOL 3,5-BISPHOSPHATE, DIRECTLY PHOSPHORYLATES, KYNURENINE PATHWAY, TELOMERE LENGTH, SCHIZOPHRENIA, DEMENTIA, LITHIUM, LOCI

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