Cited by 328Alzheimer's disease research and treatmentsGenetic Associations and EpidemiologyDementia and Cognitive Impairment Research

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Alzheimer’s Disease: Analyzing the Missing Heritability

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Ridge, Perry G., Mukherjee, Shubhabrata, Crane, Paul K., Kauwe, John S. K., Alzheimer’s Disease Genetics Consortium·2013·PLoS ONE

DOI 10.1371/journal.pone.0079771PMC PMC3820606

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Abstract

Alzheimer's disease (AD) is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to analyze >2 million SNPs for 10,922 individuals from the Alzheimer's Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer's Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer's disease.

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Suicide
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Depression
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Chronic Pain
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Preface
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Health Policy Implications
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Introduction
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Alzheimer’s Disease and Other Dementias
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Immune Function
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Heart Disease
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Cancer
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Diet and Weight
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Dedication
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Personality Traits and Disorders
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Schizophrenia and Other Psychoses
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Authors: Ridge, P. G., Mukherjee, S., Crane, P. K., Kauwe, J. S. K., & Alzheimer’s Disease Genetics Consortium
Affiliations: Brigham Young University (US)
University of Washington (US)
Corresponding author: Kauwe, John S. K.
ORCID: Ridge, Perry G.
Mukherjee, Shubhabrata
Crane, Paul K.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2013-11-07
Volume: 8
Issue: 11
Pages: e79771
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0079771
PMC: PMC3820606
OpenAlex: W2010192073
Cited by: 328
References: 64
Citations by year: 2026: 8 · 2025: 13 · 2024: 18 · 2023: 60 · 2022: 26 · 2021: 31 · 2020: 29 · 2019: 24 · 2018: 29 · 2017: 26 · 2016: 30 · 2015: 22 · 2014: 12
FWCI: 14.70
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Howard Hughes Medical Institute
U.S. Department of Veterans Affairs (U01 AG024904)
Alzheimer's Association (IIRG-05–14147, K01 AG030514, U01 AG016976, R01AG042611, U01 AG032984, IIRG-08-89720, U01 AG024904, U24AG021886, MNIRG-11-205368)
Dana Foundation (K01 AG030514, U01 AG024904)
Bristol-Myers Squibb (U01 AG024904, AG024904)
Eli Lilly and Company (U01 AG024904, AG024904)
Pfizer (AG024904, U01 AG024904)
AstraZeneca
GlaxoSmithKline
Novartis
Office of Research and Development
Brigham Young University (MNIRG-11-205368, R01AG042611)
University of Pennsylvania (U24 AG026395, U24 AG026390)
F. Hoffmann-La Roche (AG024904, U01 AG024904)
Medpace (U01 AG024904)
Synarc (U01 AG024904, K01 AG030514)
Northern California Institute for Research and Education (U01 AG024904, K01 AG030514)
Wellcome Trust
Alzheimer's Research Trust
Newcastle University
Stichting MS Research
Elan (U01 AG024904)
Eisai (U01 AG024904, AG024904)
North Bristol NHS Trust
Universitat de Barcelona
Hersenstichting
National Institutes of Health (5rc2ag036502-02, MNIRG-11-205368, 5r01ag027944-05, 5u01ag024904-10, 7r01ag019757-06, 5r37ag015473-15, AG016976, U01-AG024904, AG024904, MH60451)
Genentech (AG024904, U01 AG024904)
Canadian Institutes of Health Research
Medical Research Council (U01 AG024904, K01 AG030514)
National Institute on Aging (U01-AG-024904, R01AG017917, AG 10483, P01AG010491, P50 AG016575, AG 016976, AG05 128, P30AG010129, P30AG010133, R01AG019085, P50AG005144, R01AG042611, P50 AG016576, R01AG030146, AG021547, AG036535, AG010491, AG-05144, U24 AG026390, P30AG028383, P30AG012300, AG 025688, P50AG016577, P50AG005133, R01-AG027944, AG 024904, AG 030,514, AG-034504, P30AG028377, U01AG006781, U01AG016976, P50AG005131, R01-AG019757, R01AG034504, R37-AG015473, P50AG005138, R01AG026390, R01AG022374, P50AG016570, AG019610, K01AG030514, R01AG040770, AG036528, P50AG005128, P30AG010124, P50AG016573, AG019757, R01AG021547, R01AG041232, R01AG030653, U01AG010483, R01AG015819, P30AG008017, P30AG010161, U01AG032984, R01AG012101, R01AG031581, P30AG008051, R01AG041797, RC2-AG036502, P50AG016582, P50AG008702, AG032984, AG013846, P50AG005681, P50AG005142, P50AG008671, P30AG019610, R01AG026916, P50AG005146, P01AG003991, 1RC2AG036502, U24AG026395, P30AG013846, P50AG005136, P50AG005134, RC2AG036535, P30AG013854, R01AG025259, P50AG025688, AG026395, R01AG017173, RC2AG036528, R01AG033193, P01AG002219, AG021886, R01AG013616, U24AG056270, P01AG019724, U24AG021886, P30AG062421, P50AG023501, AG027944, R01AG020688, AG 030653, P50AG016574, R01AG035137, UO1-AG06781)
National Institute of Mental Health (U01 AG024904, MH60451, R01MH080295, P50MH060451)
National Human Genome Research Institute (UO1 HG004610, U01HG004610, U01HG006375)
National Cancer Institute (R01CA129769, U54CA137788, U54CA132378)
National Institute of Neurological Disorders and Stroke (NS3 9764, R01NS080820, R01NS059873, MH60451, NIMH MH60451, P50NS039764)
National Institute of Biomedical Imaging and Bioengineering (U01 AG024904, AG024904)
National Center for Research Resources (MO1 RR000-96, UL1RR02777, UL1RR029893, M01RR000096, M01RR000645)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, missing heritability, phenotypic variance explained, GCTA, common SNPs, apolipoprotein E, genetic markers
MeSH terms: Aged, Alzheimer Disease, Apolipoproteins E, Female, Genetic Markers, Humans, Male, Case-Control Studies, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study

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