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Alzheimer's disease: analyzing the missing heritability.

TitleAlzheimer's disease: analyzing the missing heritability.
Publication TypeJournal Article
Year of Publication2013
AuthorsRidge, PG, Mukherjee, S, Crane, PK, Kauwe, JSK
Corporate AuthorsAlzheimer’s Disease Genetics Consortium
JournalPLoS One
Volume8
Issue11
Paginatione79771
Date Published2013
ISSN1932-6203
KeywordsAge of Onset, Aged, Alzheimer Disease, Apolipoproteins E, Case-Control Studies, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci
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.

DOI10.1371/journal.pone.0079771
Alternate JournalPLoS ONE
PubMed ID24244562
PubMed Central IDPMC3820606
Grant ListK01 AG030514 / AG / NIA NIH HHS / United States
MH60451 / MH / NIMH NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R01 AG040770 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
M01 RR000645 / RR / NCRR NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
U01 AG10483 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01AG042611 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
P50 AG016577 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
R01 AG020688 / AG / NIA NIH HHS / United States
R01 AG017173 / AG / NIA NIH HHS / United States
P50 AG016575 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
P30 AG028377 / AG / NIA NIH HHS / United States
AG05128 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
UO1 HG004610 / HG / NHGRI NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
1R01AG035137 / AG / NIA NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
RC2 AG036535 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
P30 AG08051 / AG / NIA NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
5R01AG022374 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01AG33193 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
U24 AG026390 / AG / NIA NIH HHS / United States
1RC2AG036502 / AG / NIA NIH HHS / United States
UO1 AG06781 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
AG05144 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R01 CA129769 / CA / NCI NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 AG041797 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
5R01AG012101 / AG / NIA NIH HHS / United States
AG034504 / AG / NIA NIH HHS / United States
R01 AG30146 / AG / NIA NIH HHS / United States
R37 AG015473 / AG / NIA NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
R01 NS059873 / NS / NINDS NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
5R01AG013616 / AG / NIA NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
P30 AG013854 / AG / NIA NIH HHS / United States
P50 AG016576 / AG / NIA NIH HHS / United States
AG019757 / AG / NIA NIH HHS / United States
MO1RR00096 / RR / NCRR NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
/ / Wellcome Trust / United Kingdom
AG021547 / AG / NIA NIH HHS / United States
UL1RR02777 / RR / NCRR NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States