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Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain

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, characteri...

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Autores principales: Monereo-Sánchez, Jennifer, Schram, Miranda T., Frei, Oleksandr, O’Connell, Kevin, Shadrin, Alexey A., Smeland, Olav B., Westlye, Lars T., Andreassen, Ole A., Kaufmann, Tobias, Linden, David E. J., van der Meer, Dennis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288283/
https://www.ncbi.nlm.nih.gov/pubmed/34290577
http://dx.doi.org/10.3389/fnins.2021.653130
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author Monereo-Sánchez, Jennifer
Schram, Miranda T.
Frei, Oleksandr
O’Connell, Kevin
Shadrin, Alexey A.
Smeland, Olav B.
Westlye, Lars T.
Andreassen, Ole A.
Kaufmann, Tobias
Linden, David E. J.
van der Meer, Dennis
author_facet Monereo-Sánchez, Jennifer
Schram, Miranda T.
Frei, Oleksandr
O’Connell, Kevin
Shadrin, Alexey A.
Smeland, Olav B.
Westlye, Lars T.
Andreassen, Ole A.
Kaufmann, Tobias
Linden, David E. J.
van der Meer, Dennis
author_sort Monereo-Sánchez, Jennifer
collection PubMed
description 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 × 10(–4)) and depression (B = 0.007, p = 3.2 × 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 × 10(–4)), third ventricle volume ventricle (B = −0.025, p = 5.0 × 10(–6)), and inferior temporal gyrus surface area (B = 0.017, p = 5.3 × 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.
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spelling pubmed-82882832021-07-20 Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain Monereo-Sánchez, Jennifer Schram, Miranda T. Frei, Oleksandr O’Connell, Kevin Shadrin, Alexey A. Smeland, Olav B. Westlye, Lars T. Andreassen, Ole A. Kaufmann, Tobias Linden, David E. J. van der Meer, Dennis Front Neurosci Neuroscience 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 × 10(–4)) and depression (B = 0.007, p = 3.2 × 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 × 10(–4)), third ventricle volume ventricle (B = −0.025, p = 5.0 × 10(–6)), and inferior temporal gyrus surface area (B = 0.017, p = 5.3 × 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. Frontiers Media S.A. 2021-07-05 /pmc/articles/PMC8288283/ /pubmed/34290577 http://dx.doi.org/10.3389/fnins.2021.653130 Text en Copyright © 2021 Monereo-Sánchez, Schram, Frei, O’Connell, Shadrin, Smeland, Westlye, Andreassen, Kaufmann, Linden and van der Meer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Monereo-Sánchez, Jennifer
Schram, Miranda T.
Frei, Oleksandr
O’Connell, Kevin
Shadrin, Alexey A.
Smeland, Olav B.
Westlye, Lars T.
Andreassen, Ole A.
Kaufmann, Tobias
Linden, David E. J.
van der Meer, Dennis
Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain
title Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain
title_full Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain
title_fullStr Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain
title_full_unstemmed Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain
title_short Genetic Overlap Between Alzheimer’s Disease and Depression Mapped Onto the Brain
title_sort genetic overlap between alzheimer’s disease and depression mapped onto the brain
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288283/
https://www.ncbi.nlm.nih.gov/pubmed/34290577
http://dx.doi.org/10.3389/fnins.2021.653130
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