RESUMO
Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the 'Top Results' list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case-control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Idoso , Bases de Dados Genéticas , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A recent study suggested that the cadherin gene FAT exerts an influence on susceptibility to bipolar affective disorder (BPAD). We aimed to replicate this finding in a German sample (425 BPAD I and 419 controls). In addition, we performed a comprehensive linkage disequilibrium mapping of the whole genomic region of FAT and the neighboring circadian gene MTNR1A (48 single nucleotide polymorphisms (SNPs) covering 191 kb). No significant association was observed for SNPs located in the MTNR1A gene. In FAT, however, nine SNPs showed association, eight of them being located in the same haplotype block found to be associated with BPAD by Blair et al. The smallest P-value of 0.00028 (OR 1.71) was seen for non-synonymous SNP rs2637777. A combination of five markers including this marker showed a haplotype distribution with a nominal P-value of 1.8 x 10(-5) that withstands correction for multiple testing. While the control allele frequencies between our sample and the samples of the original study are comparable, tendencies of risk allele frequencies are opposite. Possible explanations for this include potential differences in linkage disequilibrium structure between the German, Australian, UK, and Bulgarian populations sampling variation, multilocus effects and/or the occurrence of independent mutational events. We conclude that our results support an involvement of variation at the FAT gene in the etiology of BPAD, but that further work is needed both to clarify possible reasons for the observed risk allele differences and to ultimately identify the functionally relevant variant(s).
Assuntos
Transtorno Bipolar/genética , Caderinas/genética , Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Mapeamento Cromossômico/métodos , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Receptor MT1 de Melatonina/genéticaRESUMO
The Tachykinin Receptor 2 (TACR2) located at chromosome 10q21.3 belongs to a class of receptors that bind members of the tachykinin neurotransmitter family. The TACR2 binds neurokinin A, also known as substance K, and is expressed in distinct parts of the human brain. Functionally, the TACR2 has been implicated in stress induced hippocampal acetylcholine release and the gene TACR2 is located within a previously identified linkage region for Alzheimer's disease (AD) on chromosome 10q21. Together, both facts make the TACR2 a reasonable positional and functional candidate gene for AD. Genotyping of 13 single nucleotide polymorphisms (SNPs) covering the entire gene and haplotypic analysis revealed no association with AD. Thus, we conclude that TACR2 can be excluded as a major susceptibility gene conferring risk to AD.