Targeted sequencing of Alzheimer disease genes in African Americans implicates novel risk variants

Mark W. Logue; Daniel Lancour; John Farrell; Irina Simkina; M. Daniele Fallin; Kathryn L. Lunetta; Lindsay A. Farrer

doi:10.3389/fnins.2018.00592

Targeted sequencing of Alzheimer disease genes in African Americans implicates novel risk variants

Mark W. Logue, Daniel Lancour, John Farrell, Irina Simkina, M. Daniele Fallin, Kathryn L. Lunetta, Lindsay A. Farrer

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10^-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p < 8.6 × 10^-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.

Original language	English (US)
Article number	592
Journal	Frontiers in Neuroscience
Volume	12
Issue number	AUG
DOIs	https://doi.org/10.3389/fnins.2018.00592
State	Published - Aug 27 2018

Keywords

ABCA7
AKAP9
African Americans
Alzheimer disease
Rare variant
Sequencing

ASJC Scopus subject areas

General Neuroscience

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10.3389/fnins.2018.00592

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@article{f372cf2f8c914fee99647a45eac0db44,

title = "Targeted sequencing of Alzheimer disease genes in African Americans implicates novel risk variants",

abstract = "The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p < 8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.",

keywords = "ABCA7, AKAP9, African Americans, Alzheimer disease, Rare variant, Sequencing",

author = "Logue, {Mark W.} and Daniel Lancour and John Farrell and Irina Simkina and Fallin, {M. Daniele} and Lunetta, {Kathryn L.} and Farrer, {Lindsay A.}",

note = "Funding Information: This study was funded in part by grants from the National Institute on Aging (NIA, R01-AG048927, P30-AG13846, U01-AG032984, UF1-AG046198, and RF1-AG057519). Some biological samples used in this study were obtained from the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University funded by NIA grant U24-AG021886. Publisher Copyright: {\textcopyright} 2018 Logue, Lancour, Farrell, Simkina, Fallin, Lunetta and Farrer.",

year = "2018",

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doi = "10.3389/fnins.2018.00592",

language = "English (US)",

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AU - Logue, Mark W.

AU - Lancour, Daniel

AU - Farrell, John

AU - Simkina, Irina

AU - Fallin, M. Daniele

AU - Lunetta, Kathryn L.

AU - Farrer, Lindsay A.

N1 - Funding Information: This study was funded in part by grants from the National Institute on Aging (NIA, R01-AG048927, P30-AG13846, U01-AG032984, UF1-AG046198, and RF1-AG057519). Some biological samples used in this study were obtained from the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University funded by NIA grant U24-AG021886. Publisher Copyright: © 2018 Logue, Lancour, Farrell, Simkina, Fallin, Lunetta and Farrer.

PY - 2018/8/27

Y1 - 2018/8/27

N2 - The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p < 8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.

AB - The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p < 8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.

KW - ABCA7

KW - AKAP9

KW - African Americans

KW - Alzheimer disease

KW - Rare variant

KW - Sequencing

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Targeted sequencing of Alzheimer disease genes in African Americans implicates novel risk variants

Abstract

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