RESUMO
The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 10/genética , Predisposição Genética para Doença , Idade de Início , Idoso , Alelos , Apolipoproteína E4 , Apolipoproteínas E/genética , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Escore Lod , Núcleo Familiar , Razão de ChancesRESUMO
Recent reports have suggested that variability in the alpha2-macroglobulin gene is a genetic risk factor for Alzheimer's disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.
Assuntos
Doença de Alzheimer/genética , Ligação Genética , Polimorfismo Genético/genética , alfa-Macroglobulinas/genética , Idade de Início , Alelos , Doença de Alzheimer/epidemiologia , Apolipoproteínas E/genética , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Humanos , Escore Lod , Pessoa de Meia-Idade , Núcleo Familiar , Polimorfismo de Fragmento de RestriçãoRESUMO
Clock gene anomalies have been suggested as causative factors in autism. We screened eleven clock/clock-related genes in a predominantly high-functioning Autism Genetic Resource Exchange sample of strictly diagnosed autistic disorder progeny and their parents (110 trios) for association of clock gene variants with autistic disorder. We found significant association (P<0.05) for two single-nucleotide polymorphisms in per1 and two in npas2. Analysis of all possible combinations of two-marker haplotypes for each gene showed that in npas2 40 out of the 136 possible two-marker combinations were significant at the P<0.05 level, with the best result between markers rs1811399 and rs2117714, P=0.001. Haplotype analysis within per1 gave a single significant result: a global P=0.027 for the markers rs2253820-rs885747. No two-marker haplotype was significant in any of the other genes, despite the large number of tests performed. Our findings support the hypothesis that these epistatic clock genes may be involved in the etiology of autistic disorder. Problems in sleep, memory and timing are all characteristics of autistic disorder and aspects of sleep, memory and timing are each clock-gene-regulated in other species. We identify how our findings may be relevant to theories of autism that focus on the amygdala, cerebellum, memory and temporal deficits. We outline possible implications of these findings for developmental models of autism involving temporal synchrony/social timing.
Assuntos
Transtorno Autístico/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Relógios Biológicos/genética , Proteínas de Ciclo Celular/genética , Proteínas do Tecido Nervoso/genética , Adulto , Epistasia Genética , Feminino , Haplótipos , Humanos , Masculino , Linhagem , Proteínas Circadianas Period , Polimorfismo de Nucleotídeo Único , Comportamento Social , Percepção do Tempo/fisiologiaRESUMO
BACKGROUND: Alzheimer's disease manifests considerable heterogeneity, the cause of which is unknown. AIMS: To determine the familial (genotypic) influence on phenomenology (phenotype) in Alzheimer's disease. METHOD: Affected sibling pairs with Alzheimer's disease were assessed for a range of cognitive and non-cognitive symptoms. Resemblance for phenotypic characteristics was estimated using intraclass correlations for continuous traits and by pairwise concordance for dichotomous traits. The relationship between age of onset and APOE genotype was examined using linear regression analysis. RESULTS: Significant familial effects on age of onset (intraclass correlation 0.41) and mood state (intraclass correlation 0.26), and a relatively high pairwise concordance for agitation (excess concordance 0.1) were found. The APOE locus was found to account for 4% of the variance in age of onset. CONCLUSIONS: Substantial familial influence on age of onset, depression and agitation suggests that genotype does influence phenotype in Alzheimer's disease. Establishing the molecular basis for this phenotypic variation may prove relevant to other neuropsychiatric disorders.