TY - JOUR
T1 - Genetic Overlap Between Alzheimer's Disease and Depression Mapped Onto the Brain
AU - Monereo-Sanchez, Jennifer
AU - Schram, Miranda T.
AU - Frei, Oleksandr
AU - O'Connell, Kevin
AU - Shadrin, Alexey A.
AU - Smeland, Olav B.
AU - Westlye, Lars T.
AU - Andreassen, Ole A.
AU - Kaufmann, Tobias
AU - Linden, David E. J.
AU - van der Meer, Dennis
N1 - Funding Information:
This work was partly performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) (tsd-drift@usit.uio.no). We would like to thank the research participants and employees of 23 and Me for making this work possible. Funding. The authors were funded by the Research Council of Norway (276082, 213837, 223273, 204966/F20, 229129, 249795/F20, 225989, 248778, 249795, 298646, and 300767), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-064, and 2017-004), Stiftelsen Kristian Gerhard Jebsen (SKGJ-Med-008), the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (ERC Starting Grant, Grant agreement No. 802998) and National Institutes of Health (R01MH100351 and R01GM104400).
Funding Information:
The authors were funded by the Research Council of Norway (276082, 213837, 223273, 204966/F20, 229129, 249795/F20, 225989, 248778, 249795, 298646, and 300767), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-064, and 2017-004), Stiftelsen Kristian Gerhard Jebsen (SKGJ-Med-008), the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (ERC Starting Grant, Grant agreement No. 802998) and National Institutes of Health (R01MH100351 and R01GM104400).
Publisher Copyright:
© Copyright © 2021 Monereo-Sánchez, Schram, Frei, O’Connell, Shadrin, Smeland, Westlye, Andreassen, Kaufmann, Linden and van der Meer.
PY - 2021/7/5
Y1 - 2021/7/5
N2 - Background: Alzheimer's disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterising their genetic overlap may provide aetiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects. Methods: We applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD (n = 79,145) and depression (n = 450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (UKB) (mean age 57.21, 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data. Results: MiXer estimated 98 causal genetic variants overlapping between the 2 disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD (B = -0.002, p = 9.1 x 10(-4)) and depression (B = 0.007, p = 3.2 x 10(-9)) in the UKB. This SNP was also associated with several regions of the corpus callosum volume anterior (B > 0.024, p < 8.6 x 10(-4)), third ventricle volume ventricle (B = -0.025, p = 5.0 x 10(-6)), and inferior temporal gyrus surface area (B = 0.017, p = 5.3 x 10(-4)). Discussion: Our results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.
AB - Background: Alzheimer's disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterising their genetic overlap may provide aetiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects. Methods: We applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD (n = 79,145) and depression (n = 450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (UKB) (mean age 57.21, 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data. Results: MiXer estimated 98 causal genetic variants overlapping between the 2 disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD (B = -0.002, p = 9.1 x 10(-4)) and depression (B = 0.007, p = 3.2 x 10(-9)) in the UKB. This SNP was also associated with several regions of the corpus callosum volume anterior (B > 0.024, p < 8.6 x 10(-4)), third ventricle volume ventricle (B = -0.025, p = 5.0 x 10(-6)), and inferior temporal gyrus surface area (B = 0.017, p = 5.3 x 10(-4)). Discussion: Our results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.
KW - Alzheimer's disease
KW - CORPUS-CALLOSUM
KW - DEMENTIA
KW - HIPPOCAMPAL VOLUME
KW - LATE-LIFE DEPRESSION
KW - MAJOR DEPRESSION
KW - METAANALYSIS
KW - MRI
KW - RISK-FACTOR
KW - SYMPTOMS
KW - TEMPORAL-LOBE
KW - genetic overlap
KW - genome-wide association study
KW - major depression
KW - neuroimaging
KW - EPIDEMIOLOGY
U2 - 10.3389/fnins.2021.653130
DO - 10.3389/fnins.2021.653130
M3 - Article
C2 - 34290577
SN - 1662-453X
VL - 15
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
M1 - 653130
ER -