Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

Alzheimer’s Disease Sequencing Project

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17 Citations (Scopus)

Abstract

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Exome
Alzheimer Disease
Hispanic Americans
Genes
Long Noncoding RNA
Genome
Immunoglobulin Genes
Zinc Fingers
Amyloid
Haplotypes
Nucleotides
Antibodies

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

@article{4c578309f7e541679f81ec3d2765b6b1,
title = "Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation",
abstract = "The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.",
author = "{Alzheimer’s Disease Sequencing Project} and Bis, {Joshua C.} and Xueqiu Jian and Kunkle, {Brian W.} and Yuning Chen and Hamilton-Nelson, {Kara L.} and Bush, {William S.} and Salerno, {William J.} and Daniel Lancour and Yiyi Ma and Renton, {Alan E.} and Edoardo Marcora and Farrell, {John J.} and Yi Zhao and Liming Qu and Shahzad Ahmad and Najaf Amin and Philippe Amouyel and Beecham, {Gary W} and Below, {Jennifer E.} and Dominique Campion and Camille Charbonnier and Jaeyoon Chung and Crane, {Paul K.} and Carlos Cruchaga and Cupples, {L. Adrienne} and Dartigues, {Jean Fran{\cc}ois} and St{\'e}phanie Debette and Deleuze, {Jean Fran{\cc}ois} and Lucinda Fulton and Gabriel, {Stacey B.} and Emmanuelle Genin and Gibbs, {Richard A.} and Alison Goate and Benjamin Grenier-Boley and Namrata Gupta and Haines, {Jonathan L.} and Havulinna, {Aki S.} and Seppo Helisalmi and Mikko Hiltunen and Howrigan, {Daniel P.} and Ikram, {M. Arfan} and Jaakko Kaprio and Jan Konrad and Amanda Kuzma and Lander, {Eric S.} and Mark Lathrop and Terho Lehtim{\"a}ki and Pericak-Vance, {Margaret A} and Mike Schmidt and Martin, {Eden R}",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41380-018-0112-7",
language = "English (US)",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

AU - Alzheimer’s Disease Sequencing Project

AU - Bis, Joshua C.

AU - Jian, Xueqiu

AU - Kunkle, Brian W.

AU - Chen, Yuning

AU - Hamilton-Nelson, Kara L.

AU - Bush, William S.

AU - Salerno, William J.

AU - Lancour, Daniel

AU - Ma, Yiyi

AU - Renton, Alan E.

AU - Marcora, Edoardo

AU - Farrell, John J.

AU - Zhao, Yi

AU - Qu, Liming

AU - Ahmad, Shahzad

AU - Amin, Najaf

AU - Amouyel, Philippe

AU - Beecham, Gary W

AU - Below, Jennifer E.

AU - Campion, Dominique

AU - Charbonnier, Camille

AU - Chung, Jaeyoon

AU - Crane, Paul K.

AU - Cruchaga, Carlos

AU - Cupples, L. Adrienne

AU - Dartigues, Jean François

AU - Debette, Stéphanie

AU - Deleuze, Jean François

AU - Fulton, Lucinda

AU - Gabriel, Stacey B.

AU - Genin, Emmanuelle

AU - Gibbs, Richard A.

AU - Goate, Alison

AU - Grenier-Boley, Benjamin

AU - Gupta, Namrata

AU - Haines, Jonathan L.

AU - Havulinna, Aki S.

AU - Helisalmi, Seppo

AU - Hiltunen, Mikko

AU - Howrigan, Daniel P.

AU - Ikram, M. Arfan

AU - Kaprio, Jaakko

AU - Konrad, Jan

AU - Kuzma, Amanda

AU - Lander, Eric S.

AU - Lathrop, Mark

AU - Lehtimäki, Terho

AU - Pericak-Vance, Margaret A

AU - Schmidt, Mike

AU - Martin, Eden R

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

AB - The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

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U2 - 10.1038/s41380-018-0112-7

DO - 10.1038/s41380-018-0112-7

M3 - Article

AN - SCOPUS:85052493500

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -