Premium
O3–01–05: The role of functional genetic variation in Alzheimer's disease: The CHARGE consortium
Author(s) -
Jakobsdottir Johanna,
Bis Joshua,
IbrahimVerbaas Carla,
Chouraki Vincent,
Destefano Anita,
Lee Sven,
GroveGaona Megan,
Smith Albert,
Launer Lenore,
Hofman Albert,
Uitterlinden André,
Ikram Mohammad,
O'Donnell Christopher,
Boerwinkle Eric,
Fitzpatrick Annette,
Seshadri Sudha,
Gudnason Vilmundur,
Duijn Cornelia
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.04.240
Subject(s) - minor allele frequency , single nucleotide polymorphism , genetics , genome wide association study , heritability , biology , genetic association , missing heritability problem , exome , genetic variation , genotype , psen1 , allele frequency , genotyping , snp , allele , exome sequencing , alzheimer's disease , gene , disease , medicine , mutation , amyloid precursor protein
For validation, we performed gene-based case-control association testing in 13,748 individuals (7,652 affected) from the Alzheimer’s Disease Genetics Consortium (ADGC) genotyped on the Illumina Exome SNPArray, which included 195,039 variants with MAF<2%. Results: In each pedigree, 4-18 variants passed stringent filtering criteria (e.g., evolutionary conservation, predicted deleteriousness, identity-by-descent >75%). as potential causative LOAD variants. Examining the 60 genes implicated by these variants, five (CAPZA3, LONRF3, LRP1B, MYO3B and TBC1D17) showed nominally significant associations in gene-based tests in the ADGC dataset, with CAPZA3 and TBC1D17 withstanding correction for multiple comparison.CAPZA3 is located in the published chromosome 12 AD linkage region and encodes an actin-capping protein that stabilizes actin filaments and TBC1D17 is a Rab GTPase-activating protein implicated in endocytosis, both AD-relevant processes. Moreover, LRP1B is a low-density lipoprotein receptor that allows endocytosis of a complex of ApoE-containing lipoprotein particles bound to beta-amyloid. Conclusions: Identifying LOAD candidates from whole exome sequencing of extended LOAD families is challenging due to reduced penetrance, potential phenotypic heterogeneity and rarity of candidate alleles. Here we mitigated these challenges by validating candidates using gene-based association testing in a large consortium dataset, identifying several new LOAD candidate genes.