Evidence map›Paper›PMID 22685416›Full record

SynthesisPLoS genetics2012

Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants.

Fanggeng Zou, High Seng Chai, Curtis S Younkin, Mariet Allen, Julia Crook, V Shane Pankratz, Minerva M Carrasquillo, Christopher N Rowley, Asha A Nair, Sumit Middha and 22 more

Abstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 153 papers, 16 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
153citing papers in PubMed, 16 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

153 citing papers in PubMed, 16 syntheses or guidelines pooled it.

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  3. A Meta-Analysis of Alzheimer's Disease Brain Transcriptomic Data.Journal of Alzheimer's disease : JAD · 2019
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93 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

32 authors.

Fanggeng ZouDepartment of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
High Seng Chai
Curtis S Younkin
Mariet Allen
Julia Crook
V Shane Pankratz
Minerva M Carrasquillo
Christopher N Rowley
Asha A Nair
Sumit Middha
Sooraj Maharjan
Thuy Nguyen
Li Ma
Kimberly G Malphrus
Ryan Palusak
Sarah Lincoln
Gina Bisceglio
Constantin Georgescu
Naomi Kouri
Christopher P Kolbert
Jin Jen
Jonathan L Haines
Richard Mayeux
Margaret A Pericak-Vance
Lindsay A Farrer
Gerard D Schellenberg
Alzheimer's Disease Genetics Consortium
Ronald C Petersen
Neill R Graff-Radford
Dennis W Dickson
Steven G Younkin
Nilüfer Ertekin-Taner

Funding

Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
TRIAL OF VALPROATE TO ATTENUATE THE PROGRESSION OF ADU01AG010483 · NIA · UNIVERSITY OF ROCHESTER · PI AISEN, PAUL S. · 1991 to 2012
$116.2M
RECRUITMENT COREU19AG010483 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FELDMAN, HOWARD · 2013 to 2020
$80.6M
Vascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Richard B. LIPTON · 1985 to 2026
$73.9M
NATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8M
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI Tammie Lee Smith Benzinger · 1985 to 2026
$69.5M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
THERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI JAYADEY, SUMAN · 1985 to 2019
$57.2M
VIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BREWER, JAMES B · 1985 to 2018
$55.4M
WASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1M
CIHRHoward Hughes Medical InstituteMedical Research Council G0701075Medical Research Council G0901254Medical Research Council MC_G1000734Medical Research Council MR/K01417X/1NCATS NIH HHS UL1 TR000117NCATS NIH HHS UL1 TR001998NCI NIH HHS R01 CA129769NCI NIH HHS U54 CA132378NCI NIH HHS U54 CA137788NCRR NIH HHS KL2 RR024151NCRR NIH HHS M01 RR000096NCRR NIH HHS MO1RR00096NCRR NIH HHS UL1RR02777NCRR NIH HHS UL1 RR029893NHGRI NIH HHS R01 HG002213NHGRI NIH HHS R01 HG02213NHGRI NIH HHS U01 HG004610NHGRI NIH HHS U01 HG006375NHGRI NIH HHS UO1 HG004610NIA NIH HHS AG003949NIA NIH HHS AG010491NIA NIH HHS AG017216NIA NIH HHS AG019757NIA NIH HHS AG021547NIA NIH HHS AG025688NIA NIH HHS AG025711NIA NIH HHS AG027944NIA NIH HHS AG030653NIA NIH HHS AG17586NIA NIH HHS K01 AG030514NIA NIH HHS K23 AG034550NIA NIH HHS K24 AG027841NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG010491NIA NIH HHS P01 AG017216NIA NIH HHS P01 AG017586NIA NIH HHS P01 AG019724NIA NIH HHS P01 AG03991NIA NIH HHS P30 AG008017NIA NIH HHS P30 AG008051NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010129NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG012300NIA NIH HHS P30 AG013846NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG028377NIA NIH HHS P30 AG028383NIA NIH HHS P30 AG08051NIA NIH HHS P30 AG10133NIA NIH HHS P30 AG1961NIA NIH HHS P50 AG005128NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005134NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG005142NIA NIH HHS P50 AG005144NIA NIH HHS P50 AG005146NIA NIH HHS P50 AG005681NIA NIH HHS P50 AG008671NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016570NIA NIH HHS P50 AG016573NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG016575NIA NIH HHS P50 AG016576NIA NIH HHS P50 AG016577NIA NIH HHS P50 AG016582NIA NIH HHS P50 AG023501NIA NIH HHS P50 AG025688NIA NIH HHS P50 AG025711NIA NIH HHS R01 AG009029NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017173NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG018023NIA NIH HHS R01 AG019085NIA NIH HHS R01 AG019757NIA NIH HHS R01 AG020688NIA NIH HHS R01 AG021547NIA NIH HHS R01 AG025259NIA NIH HHS R01 AG026390NIA NIH HHS R01 AG026916NIA NIH HHS R01 AG027944NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG030653NIA NIH HHS R01 AG031581NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG040770NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG15819NIA NIH HHS R01 AG17917NIA NIH HHS R01 AG30146NIA NIH HHS R37 AG015473NIA NIH HHS RC2 AG036528NIA NIH HHS RC2 AG036535NIA NIH HHS U01 AG006576NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG010483NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG10483NIA NIH HHS U19 AG010483NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG026390NIA NIH HHS U24 AG026395NIA NIH HHS U24 AG056270NIA NIH HHS UO1 AG06781NIGMS NIH HHS T32 GM007754NIMH NIH HHS P50 MH060451NIMH NIH HHS R01 MH080295NINDS NIH HHS P50 NS039764NINDS NIH HHS R01 NS059873NINDS NIH HHS U24 NS072026Wellcome Trust 081864Wellcome Trust 089703
6 · The paper itself

Abstract

Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5)-1.67 × 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5)-1.70 × 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.

Indexed as

Gene Expression RegulationGenome-Wide Association StudyTemporal LobeAlzheimer DiseaseAutopsyGenetic Predisposition to DiseaseGenotypeHumansPolymorphism, Single NucleotideRNARNA

Identifiers

PMID22685416
PMCPMC3369937

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