Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

• DOI: 10.1038/mp.2012.14
• Publication Date: 2012-03-20T09:19:54Z
• Authors: J-C Lambert; B Grenier-Boley; D Harold; D Zelenika; V Chouraki; Y Kamatani; K Sleegers; M A Ikram; M Hiltunen; C Reitz; I Mateo; T Feulner; M Bullido; D Galimberti; L Concari; V Alvarez; R Sims; A Gerrish; J Chapman; C Deniz-Naranjo; V Solfrizzi; S Sorbi; B Arosio; G Spalletta; G Siciliano; J Epelbaum; D Hannequin; J-F Dartigues; C Tzourio; C Berr; E M C Schrijvers; R Rogers; G Tosto; F Pasquier; K Bettens; C Van Cauwenberghe; L Fratiglioni; C Graff; M Delepine; R Ferri; C A Reynolds; L Lannfelt; M Ingelsson; J A Prince; C Chillotti; A Pilotto; D Seripa; A Boland; M Mancuso; P Bossù; G Annoni; B Nacmias; P Bosco; F Panza; F Sanchez-Garcia; M Del Zompo; E Coto; M Owen; M O'Donovan; F Valdivieso; P Caffara; E Scarpini; O Combarros; L Buée; D Campion; H Soininen; M Breteler; M Riemenschneider; C Van Broeckhoven; A Alpérovitch; M Lathrop; D-A Trégouët; J Williams; P Amouyel
• Keywords: Genome-wide Association Study; Genetic Association; SNP; 1000 Genomes Project; Tag SNP; Multiple comparisons problem; Linkage Disequilibrium

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci genetic susceptibility in Alzheimer's disease (AD). However, landscape AD is far away be complete and addition single-SNP (single-nucleotide polymorphism) analyses as performed conventional GWAS, complementary strategies need applied overcome limitations inherent this type approaches. We a haplotype (GWHA) study EADI1 (n=2025 cases 5328 controls) by applying sliding-windows approach. After exclusion already known involved (APOE, BIN1 CR1), 91 regions with suggestive effects were identified. In second step, we attempted replicate best associations GERAD1 consortium (2820 6356 observed that 9 them showed nominal association. third tested relevant combined analysis five additional case-control (5093 4061 controls). consistently replicated within FRMD4A on Chr.10p13 all data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). finally searched for between SNPs locus Aβ plasma concentrations three independent non-demented populations (n=2579). reported polymorphisms associated Aβ42/Aβ40 ratio (best signal, P=5.4 10(-7)). conclusion, combining both GWHA conservative three-stage replication approach, characterised risk factor AD.