Dataset Information

Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

ABSTRACT:

Objective

Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.

Methods

We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.

Results

CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).

Conclusions

CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

SUBMITTER: Allen M

PROVIDER: S-EPMC3398432 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Publications

Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

Allen Mariet M Zou Fanggeng F Chai High Seng HS Younkin Curtis S CS Crook Julia J Pankratz V Shane VS Carrasquillo Minerva M MM Rowley Christopher N CN Nair Asha A AA Middha Sumit S Maharjan Sooraj S Nguyen Thuy T Ma Li L Malphrus Kimberly G KG Palusak Ryan R Lincoln Sarah S Bisceglio Gina G Georgescu Constantin C Schultz Debra D Rakhshan Fariborz F Kolbert Christopher P CP Jen Jin J Haines Jonathan L JL Mayeux Richard R Pericak-Vance Margaret A MA Farrer Lindsay A LA Schellenberg Gerard D GD Petersen Ronald C RC Graff-Radford Neill R NR Dickson Dennis W DW Younkin Steven G SG Ertekin-Taner Nilüfer N Apostolova Liana G LG Arnold Steven E SE Baldwin Clinton T CT Barber Robert R Barmada Michael M MM Beach Thomas T Beecham Gary W GW Beekly Duane D Bennett David A DA Bigio Eileen H EH Bird Thomas D TD Blacker Deborah D Boeve Bradley F BF Bowen James D JD Boxer Adam A Burke James R JR Buros Jacqueline J Buxbaum Joseph D JD Cairns Nigel J NJ Cantwell Laura B LB Cao Chuanhai C Carlson Chris S CS Carney Regina M RM Carroll Steven L SL Chui Helena C HC Clark David G DG Corneveaux Jason J Cotman Carl W CW Crane Paul K PK Cruchaga Carlos C Cummings Jeffrey L JL De Jager Philip L PL DeCarli Charles C DeKosky Steven T ST Demirci F Yesim FY Diaz-Arrastia Ramon R Dick Malcolm M Dombroski Beth A BA Duara Ranjan R Ellis William D WD Evans Denis D Faber Kelley M KM Fallon Kenneth B KB Farlow Martin R MR Ferris Steven S Foroud Tatiana M TM Frosch Matthew M Galasko Douglas R DR Gallins Paul J PJ Ganguli Mary M Gearing Marla M Geschwind Daniel H DH Ghetti Bernardino B Gilbert John R JR Gilman Sid S Giordani Bruno B Glass Jonathan D JD Goate Alison M AM Green Robert C RC Growdon John H JH Hakonarson Hakon H Hamilton Ronald L RL Hardy John J Harrell Lindy E LE Head Elizabeth E Honig Lawrence S LS Huentelman Matthew J MJ Hulette Christine M CM Hyman Bradley T BT Jarvik Gail P GP Jicha Gregory A GA Jin Lee-Way LW Jun Gyungah G Kamboh M Ilyas MI Karlawish Jason J Karydas Anna A Kauwe John S K JS Kaye Jeffrey A JA Kennedy Nancy N Kim Ronald R Koo Edward H EH Kowall Neil W NW Kramer Patricia P Kukull Walter A WA Lah James J JJ Larson Eric B EB Levey Allan I AI Lieberman Andrew P AP Lopez Oscar L OL Lunetta Kathryn L KL Mack Wendy J WJ Marson Daniel C DC Martin Eden R ER Martiniuk Frank F Mash Deborah C DC Masliah Eliezer E McCormick Wayne C WC McCurry Susan M SM McDavid Andrew N AN McKee Ann C AC Mesulam Marsel M Miller Bruce L BL Miller Carol A CA Miller Joshua W JW Montine Thomas J TJ Morris John C JC Myers Amanda J AJ Naj Adam C AC Nowotny Petra P Parisi Joseph E JE Perl Daniel P DP Peskind Elaine E Poon Wayne W WW Potter Huntington H Quinn Joseph F JF Raj Ashok A Rajbhandary Ruchita A RA Raskind Murray M Reiman Eric M EM Reisberg Barry B Reitz Christiane C Ringman John M JM Roberson Erik D ED Rogaeva Ekaterina E Rosenberg Roger N RN Sano Mary M Saykin Andrew J AJ Schneider Julie A JA Schneider Lon S LS Seeley William W Shelanski Michael L ML Slifer Michael A MA Smith Charles D CD Sonnen Joshua A JA Spina Salvatore S St George-Hyslop Peter P Stern Robert A RA Tanzi Rudolph E RE Trojanowski John Q JQ Troncoso Juan C JC Tsuang Debby W DW Van Deerlin Vivianna M VM Vardarajan Badri Narayan BN Vinters Harry V HV Vonsattel Jean Paul JP Wang Li-San LS Weintraub Sandra S Welsh-Bohmer Kathleen A KA Williamson Jennifer J Woltjer Randall L RL

Neurology 20120620 3

<h4>Objective</h4>Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.<h4>Methods</h4>We mea ...[more]

PMID: 22722634

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Project description:ImportanceGenetic causes of late-onset Alzheimer disease (LOAD) are not completely explained by known genetic loci. Whole-exome and whole-genome sequencing can improve the understanding of the causes of LOAD and provide initial steps required to identify potential therapeutic targets.ObjectiveTo identify the genetic loci for LOAD across different ethnic groups.Design, setting, and participantsThis multicenter cohort study was designed to analyze whole-exome sequencing data from a multiethnic cohort using a transethnic gene-kernel association test meta-analysis, adjusted for sex, age, and principal components, to identify genetic variants associated with LOAD. A meta-analysis was conducted on the results of 2 independent studies of whole-exome and whole-genome sequence data from individuals of European ancestry. This group of European American, African American, and Caribbean Hispanic individuals participating in an urban population-based study were the discovery cohort; the additional cohorts included affected individuals and control participants from 2 publicly available data sets. Replication was achieved using independent data sets from Caribbean Hispanic families with multiple family members affected by LOAD and the International Genetics of Alzheimer Project.Main outcomes and measuresLate-onset Alzheimer disease.ResultsThe discovery cohort included 3595 affected individuals, while the additional cohorts included 5931 individuals with LOAD and 5504 control participants. Of 3916 individuals in the discovery cohort, we included 3595 individuals (1397 with LOAD and 2198 cognitively healthy controls; 2451 [68.2%] women; mean [SD] age, 80.3 [6.83] years). Another 321 individuals (8.2%) were excluded because of non-LOAD diagnosis, age younger than 60 years, missing covariates, duplicate data, or genetic outlier status. Gene-based tests that compared affected individuals (n = 7328) and control participants (n = 7702) and included only rare and uncommon variants annotated as having moderate-high functional effect supported PINX1 (8p23.1) as a locus with gene-wide significance (P = 2.81 × 10-6) after meta-analysis across the 3 studies. The PINX1 finding was replicated using data from the family-based study and the International Genetics of Alzheimer Project. Full meta-analysis of discovery and replication cohorts reached a P value of 6.16 × 10-7 for PINX1 (in 7620 affected individuals vs 7768 control participants). We also identified TREM2 in an annotation model that prioritized highly deleterious variants with a combined annotation dependent depletion greater than 20 (P= 1.0 × 10-7).Conclusions and relevanceThis gene-based, transethnic approach identified PINX1, a gene involved in telomere integrity, and TREM2, a gene with a product of an immune receptor found in microglia, as associated with LOAD. Both genes have well-established roles in aging and neurodegeneration.

Project description:IMPORTANCE:Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES:To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS:The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES:Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS:Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P <?.005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE:We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Dataset Information

Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

Objective

Methods

Results

Conclusions

Publications

Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

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