TY - JOUR
T1 - Rare variant aggregation in 148,508 exomes identifies genes associated with proxy dementia
AU - Wightman, Douglas P.
AU - Savage, Jeanne E.
AU - de Leeuw, Christiaan A.
AU - Jansen, Iris E.
AU - Posthuma, Danielle
N1 - Funding Information: DP was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). JES was supported by funding from the Amsterdam Neuroscience Alliance Project. CdL was funded by F. Hoffmann-La Roche AG. The research has been conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA. Funding Information: DP was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). DW was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). IEJ was funded by NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012). JES was supported by funding from the Amsterdam Neuroscience Alliance Project. CdL was funded by F. Hoffmann-La Roche AG. The research has been conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SurfSARA. Publisher Copyright: © 2023, The Author(s).
PY - 2023/2/7
Y1 - 2023/2/7
N2 - Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimer’s disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimer’s disease through rare variants. Here we show that a proxy Alzheimer’s disease/dementia phenotype can capture known Alzheimer’s disease risk genes through rare variant aggregation. We generated a proxy Alzheimer’s disease/dementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer’s disease/dementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimer’s disease/dementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimer’s disease (SORL1, TREM2, and TOMM40/APOE). We show that proxy Alzheimer’s disease/dementia can be used to identify genes associated with Alzheimer’s disease through rare variant aggregation.
AB - Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimer’s disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimer’s disease through rare variants. Here we show that a proxy Alzheimer’s disease/dementia phenotype can capture known Alzheimer’s disease risk genes through rare variant aggregation. We generated a proxy Alzheimer’s disease/dementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer’s disease/dementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimer’s disease/dementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimer’s disease (SORL1, TREM2, and TOMM40/APOE). We show that proxy Alzheimer’s disease/dementia can be used to identify genes associated with Alzheimer’s disease through rare variant aggregation.
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UR - http://www.scopus.com/inward/citedby.url?scp=85147595203&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41598-023-29108-8
DO - https://doi.org/10.1038/s41598-023-29108-8
M3 - Article
C2 - 36750708
SN - 2045-2322
VL - 13
SP - 1
EP - 10
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 2179
ER -