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The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

ABSTRACT: The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ?4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ?4 allele of the APOE gene.

SUBMITTER: Lambert JC

PROVIDER: S-EPMC2964875 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

Lambert Jean-Charles JC Sleegers Kristel K González-Pérez Antonio A Ingelsson Martin M Beecham Gary W GW Hiltunen Mikko M Combarros Onofre O Bullido Maria J MJ Brouwers Nathalie N Bettens Karolien K Berr Claudine C Pasquier Florence F Richard Florence F Dekosky Steven T ST Hannequin Didier D Haines Jonathan L JL Tognoni Gloria G Fiévet Nathalie N Dartigues Jean-François JF Tzourio Christophe C Engelborghs Sebastiaan S Arosio Beatrice B Coto Elicer E De Deyn Peter P Del Zompo Maria M Mateo Ignacio I Boada Merce M Antunez Carmen C Lopez-Arrieta Jesus J Epelbaum Jacques J Schjeide Brit-Maren Michaud BM Frank-Garcia Ana A Giedraitis Vilmentas V Helisalmi Seppo S Porcellini Elisa E Pilotto Alberto A Forti Paola P Ferri Raffaele R Delepine Marc M Zelenika Diana D Lathrop Mark M Scarpini Elio E Siciliano Gabriele G Solfrizzi Vincenzo V Sorbi Sandro S Spalletta Gianfranco G Ravaglia Giovanni G Valdivieso Fernando F Vepsäläinen Saila S Alvarez Victoria V Bosco Paolo P Mancuso Michelangelo M Panza Francesco F Nacmias Benedetta B Bossù Paola P Hanon Olivier O Piccardi Paola P Annoni Giorgio G Mann David D Marambaud Philippe P Seripa Davide D Galimberti Daniela D Tanzi Rudolph E RE Bertram Lars L Lendon Corinne C Lannfelt Lars L Licastro Federico F Campion Dominique D Pericak-Vance Margaret A MA Soininen Hilkka H Van Broeckhoven Christine C Alpérovitch Annick A Ruiz Agustin A Kamboh M Ilyas MI Amouyel Philippe P

Journal of Alzheimer's disease : JAD 20100101 1

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, It ...[more]

PMID: 20847397

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Project description:Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27-74 years in carriers of the G4C2-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q < 0.05). Next, genetic analysis validated the association of rs4970944 with age of onset in the discovery (n = 469; P = 0.025) and replication (n = 4160; P = 0.007) ALS cohorts. A meta-analysis of the cohorts combined showed that the median onset in AA-carriers is two years later than in GG-carriers (n = 4629; P = 0.0012). A similar association was observed with its tagging SNPs, implicating a 16 Kb region at the 1q21.3 locus as a modifier of ALS age of onset. Notably, rs4970944 genotypes are also associated with age of onset in C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.

Dataset Information

The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

Publications

The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

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