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

Psychiatric Genomics Consortium Bipolar Disorder Working Group, Danielle Posthuma

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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
Pages (from-to)220
JournalFrontiers in Neuroscience
Publication statusPublished - 2019


We would like to thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chips was funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer’s Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG-12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association grant ADGC- 10-196728. We would like to thank the Psychiatric Genetic Consortium 2 Bipolar Disorder Working Group (PGC2-BIP) for providing summary statistics for the study. The authors are listed in the Supplementary Methods 1.5. We would also like to thank the Human Brain Transcriptome atlas for giving permission to use their figures on spatio-temporal cerebral expression of the genes identified in our study.

FundersFunder number
Competence Network Dementia01GI0711, 01GI0420, 01GI0102
Erasmus UniversityU24 AG021886, U01 AG016976, U01 AG032984
French National Foundation
National Institute on AgingR01 AG033193, AG081220
National Heart, Lung, and Blood InstituteR01 HL105756
Alzheimer's AssociationADGC- 10-196728, PGC2-BIP
Wellcome Trust082604/2/07/Z
Université de Lille
Medical Research Council503480
Institut national de la santé et de la recherche médicale
Alzheimer’s Research UK503176
Bundesministerium für Bildung und Forschung
Erasmus Medisch Centrum
Norges Idrettshøgskole
Institute Pasteur De Lille
Centre hospitalier régional universitaire de Lille


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