RESUMO
Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.
Assuntos
Modelos Lineares , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Simulação por Computador , Variação Genética , Estudo de Associação Genômica Ampla , HumanosRESUMO
The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive deterioration through pathology due to a dementing disorder or due to an aging process. Study of genetic variants in the IL1 genes has been mostly limited to diseases such as Alzheimer's, however, there may be benefit to studying a continuous measure of cognition. Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically significant minor allele SNP associations with baseline performance on the 3MS in the IL1RN gene for Caucasians (rs17042917: beta=0.47, 95%CI=0.09, 0.85, p=0.016; rs4251961: beta=-0.36, 95%CI=-0.13,-0.60, p=0.0027; rs931471: beta=0.39, 95%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African Americans (rs1143627: beta=1.6, 95%CI=0.48, 2.8; p=0.006 and rs1143634: beta=2.09, 95%CI=0.39, 3.8; p=0.016). Associations appear to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia, effect sizes and statistical significance attenuated. These results provide supporting evidence that genetic variants in IL1 genes may be involved in inflammatory-related lowered cognition, that higher education may modify genetic predisposition, and that these associations may be driven by a dementia process.
Assuntos
Cognição , Demência/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Polimorfismo de Nucleotídeo Único , Negro ou Afro-Americano/genética , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/genética , Demência/epidemiologia , Demência/metabolismo , Escolaridade , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Desequilíbrio de Ligação , Estudos Longitudinais , Masculino , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
We examined the relation between oestrogen containing hormone therapy (HT) used for more than 6 months and Alzheimer's disease (AD) risk in 971 postmenopausal women (426 AD patients, 545 relatives without dementia). There was a significant interaction between age and HT use on AD risk (p = 0.03). In stratified analyses, a significant protective association was seen only in the youngest age tertile (50-63 years; odds ratio = 0.35, 95% confidence interval = 0.19 to 0.66). Results must be considered cautiously in light of recent clinical trial evidence that oestrogen plus progestin increases dementia incidence in older postmenopausal women. However, our observational findings are consistent with the view that HT may protect younger women from AD or reduce the risk of early onset forms of AD, or that HT used during the early postmenopause may reduce AD risk.
Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/prevenção & controle , Terapia de Reposição de Estrogênios , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The associations between alcohol, smoking, and head injury and the risk of AD in 443 African American and 2,336 white participants in the MIRAGE Study were evaluated. Alcohol had a modest protective effect in whites (odds ratio [OR] = 0.82, 95% CI = 0.68 to 0.99), with a similar trend in African Americans (OR = 0.88, 95% CI = 0.54 to 1.4). Head trauma increased the risk of AD in whites (OR = 2.3, 95% CI = 1.8 to 3.0) and African Americans (OR = 2.9, 95% CI = 1.2 to 7.0). Smoking was not associated with AD risk in whites (OR = 0.88, 95% CI = 0.73 to 1.1) or African Americans (OR = 1.0, 95% CI = 0.69 to 1.5). These risks were similar across subsets stratified by the presence or absence of the APOE epsilon4 allele.
