Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2

doi:10.1038/s41380-022-01475-0

Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2

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Abstract

Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10⁻⁶, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (p_meta = 4.74 × 10⁻⁸). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (p_meta = 1 × 10⁻⁶). In conclusion, in a region-based rvGWAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.

Original language	English
Pages (from-to)	1963-1969
Number of pages	7
Journal	Molecular Psychiatry
Volume	27
Issue number	4
DOIs	https://doi.org/10.1038/s41380-022-01475-0
State	Published - Apr 2022

Bibliographical note

Funding Information:
This work was supported by Cure Alzheimer’s Fund, JPB Foundation and NIH R56AG057191 (DWF and YK). The computations in this paper were run in part on the FASRC Cannon cluster supported by the FAS Division of Science Research Computing Group at Harvard University with support from John Morrissey and in part on computers provided by Dell HPC Research Computing Solutions with support by Glen Otero. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Please refer to the Supplementary Note for full acknowledgements.

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

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10.1038/s41380-022-01475-0

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@article{9f1a9da5d0634679a370d4886c86cf60,

title = "Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer{\textquoteright}s disease-associated genes: DTNB and DLG2",

abstract = "Alzheimer{\textquoteright}s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10−6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (pmeta = 4.74 × 10−8). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta = 1 × 10−6). In conclusion, in a region-based rvGWAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.",

author = "Dmitry Prokopenko and Sanghun Lee and Julian Hecker and Kristina Mullin and Sarah Morgan and Yuriko Katsumata and Weiner, {Michael W.} and Fardo, {David W.} and Nan Laird and Lars Bertram and Winston Hide and Christoph Lange and Tanzi, {Rudolph E.}",

note = "Funding Information: This work was supported by Cure Alzheimer{\textquoteright}s Fund, JPB Foundation and NIH R56AG057191 (DWF and YK). The computations in this paper were run in part on the FASRC Cannon cluster supported by the FAS Division of Science Research Computing Group at Harvard University with support from John Morrissey and in part on computers provided by Dell HPC Research Computing Solutions with support by Glen Otero. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Please refer to the Supplementary Note for full acknowledgements. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = apr,

doi = "10.1038/s41380-022-01475-0",

language = "English",

volume = "27",

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T1 - Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes

T2 - DTNB and DLG2

AU - Prokopenko, Dmitry

AU - Lee, Sanghun

AU - Hecker, Julian

AU - Mullin, Kristina

AU - Morgan, Sarah

AU - Katsumata, Yuriko

AU - Weiner, Michael W.

AU - Fardo, David W.

AU - Laird, Nan

AU - Bertram, Lars

AU - Hide, Winston

AU - Lange, Christoph

AU - Tanzi, Rudolph E.

N1 - Funding Information: This work was supported by Cure Alzheimer’s Fund, JPB Foundation and NIH R56AG057191 (DWF and YK). The computations in this paper were run in part on the FASRC Cannon cluster supported by the FAS Division of Science Research Computing Group at Harvard University with support from John Morrissey and in part on computers provided by Dell HPC Research Computing Solutions with support by Glen Otero. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Please refer to the Supplementary Note for full acknowledgements. Publisher Copyright: © 2022, The Author(s).

PY - 2022/4

Y1 - 2022/4

N2 - Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10−6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (pmeta = 4.74 × 10−8). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta = 1 × 10−6). In conclusion, in a region-based rvGWAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.

AB - Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10−6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (pmeta = 4.74 × 10−8). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta = 1 × 10−6). In conclusion, in a region-based rvGWAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.

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SN - 1359-4184

VL - 27

SP - 1963

EP - 1969

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 4

ER -

Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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