Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 13:13:220.
doi: 10.3389/fnins.2019.00220. eCollection 2019.

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

Ole Kristian Drange  1   2 , Olav Bjerkehagen Smeland  3   4 , Alexey A Shadrin  3 , Per Ivar Finseth  5 , Aree Witoelar  3   4 , Oleksandr Frei  3 ; Psychiatric Genomics Consortium Bipolar Disorder Working Group; Yunpeng Wang  3   4 , Sahar Hassani  3   6 , Srdjan Djurovic  6   7 , Anders M Dale  8   9   10 , Ole A Andreassen  3   4
Collaborators, Affiliations

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

Ole Kristian Drange et al. Front Neurosci. .

Abstract

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.

Keywords: Alzheimer’s disease; GWAS; MARK2; VAC14; affective symptoms; bipolar disorder; cognitive symptoms; pleiotropy.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Conditional QQ-plots of nominal p-values at y-axis and 1 - empirical cumulative distribution function on x-axis for (A) Alzheimer’s disease (AD) with lines representing strata of SNPs according to their degree of association with bipolar disorder (BIP) and (B) BIP with lines representing strata of SNPs according to their degree of association with AD.
FIGURE 2
FIGURE 2
Conjunctional Manhatton plot of loci jointly associated with Alzheimer’s disease (AD) and bipolar disorder (BIP) at a conjuntional false discovery rate < 0.05.
See this image and copyright information in PMC

References

    1. Alazami A. M., Patel N., Shamseldin H. E., Anazi S., Al-dosari M. S., Alzahrani F., et al. (2015). Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10 148–161. 10.1016/j.celrep.2014.12.015 - DOI - PubMed
    1. Alfonso S. I., Callender J. A., Hooli B., Antal C. E., Mullin K., Sherman M. A., et al. (2016). Gain-of-function mutations in protein kinase Ca (PKCa) may promote synaptic defects in alzheimer’s disease. Sci. Signal. 9 1–7. 10.1126/scisignal.aaf6209 - DOI - PMC - PubMed
    1. Altshuler D. L., Durbin R. M., Abecasis G. R., Bentley D. R., Chakravarti A., Clark A. G., et al. (2010). A map of human genome variation from population-scale sequencing. Nature 467 1061–1073. 10.1038/nature09534 - DOI - PMC - PubMed
    1. Alvarez-López M. J., Molina-Martínez P., Castro-Freire M., Cosín-Tomás M., Cristòfol R., Párrizas M., et al. (2014). Rcor2 underexpression in senescent mice: a target for inflammaging? J. Neuroinflamm. 11 1–10. 10.1186/1742-2094-11-126 - DOI - PMC - PubMed
    1. Alzheimer A. (1907). Uber eine eigenartige Erkrankung der Hirnrinde. Allg. Zeitschrift Fur Psychiatr. Und Phychish-Gerichtliche Medizin 64 146–148.