Yes / Consanguineous marriage is a controversial topic in many Western societies, with attention mainly focused on the health of immigrant communities from Asia and Africa. In the UK consanguinity is especially prevalent in the Pakistani community which now numbers over 1.1 million. Less attention has been paid to the influence of hereditary population stratification within Pakistani communities. In particular, biraderi (literally brotherhood) membership which denotes male lineages that largely govern marriage partner choice and hence the transmission of disease genes. The various roles played by biraderi and their relationship to other socio-occupational and kinship terms, such as caste, quom and zat, are often overlooked in health-based studies. The interchangeable use of these different kinship terms without rigorous definition can create identity uncertainty and hinders inter-study comparisons. Where feasible, standardization of terminology would be both desirable and beneficial, with biraderi the preferred default term to identify specific social and genetic relationships within the Pakistani diaspora.

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Statistical methods that integrate between-individual (IA) and within-family (FA) genetic association analyses can increase statistical power to identify disease susceptibility genes, however combining IA and FA is valid only when the IA are free of population stratification bias (PSB). Existing methods initially test for PSB by comparing IA and FA results using an arbitrary testing level αPSB, typically 5%. Combined analyses are performed if no significant PSB is detected, otherwise analyses are restricted to FA. As a novel alternative, we propose a weighted (WGT) framework that combines the estimate from the most powerful analysis subject to PSB with the most powerful robust FA estimate, using weights based on the p-value from the PSB test. The WGT approach generalizes existing methods by using a continuous weighting function that depends only on the observed PSB p-value instead of a binary one that also depends on specification of an arbitrary PSB testing level αPSB. Simulations of quantitative trait and case-control data show that in comparison to existing methods, the WGT approach has 5% type I error closer to the nominal level, increased (decreased) accuracy for larger (smaller) PSB levels, and overall increased positive predictive value. The resulting PSB correction is SNP-specific and provides a good compromise between type I error control and power in candidate gene or confirmation studies limited to few loci, when PSB is likely and there are no additional empirical data available to correct PSB. We applied the WGT approach to a case-control study of childhood leukemia and a study of diabetes complications with time-to-event outcomes derived from repeated measurements obtained over 17 years of follow-up. To directly analyze the longitudinal measurements without specification of event thresholds, we developed fully Bayesian latent change-point time (LCPT) models for IA and FA. In analogy with the WGT approach, we also considered an extended LCPT model incorporating PSB evidence in analyses combining IA and FA.

Statistical methods that integrate between-individual (IA) and within-family (FA) genetic association analyses can increase statistical power to identify disease susceptibility genes, however combining IA and FA is valid only when the IA are free of population stratification bias (PSB). Existing methods initially test for PSB by comparing IA and FA results using an arbitrary testing level αPSB, typically 5%. Combined analyses are performed if no significant PSB is detected, otherwise analyses are restricted to FA. As a novel alternative, we propose a weighted (WGT) framework that combines the estimate from the most powerful analysis subject to PSB with the most powerful robust FA estimate, using weights based on the p-value from the PSB test. The WGT approach generalizes existing methods by using a continuous weighting function that depends only on the observed PSB p-value instead of a binary one that also depends on specification of an arbitrary PSB testing level αPSB. Simulations of quantitative trait and case-control data show that in comparison to existing methods, the WGT approach has 5% type I error closer to the nominal level, increased (decreased) accuracy for larger (smaller) PSB levels, and overall increased positive predictive value. The resulting PSB correction is SNP-specific and provides a good compromise between type I error control and power in candidate gene or confirmation studies limited to few loci, when PSB is likely and there are no additional empirical data available to correct PSB. We applied the WGT approach to a case-control study of childhood leukemia and a study of diabetes complications with time-to-event outcomes derived from repeated measurements obtained over 17 years of follow-up. To directly analyze the longitudinal measurements without specification of event thresholds, we developed fully Bayesian latent change-point time (LCPT) models for IA and FA. In analogy with the WGT approach, we also considered an extended LCPT model incorporating PSB evidence in analyses combining IA and FA.

No description available.

Fissura labial com ou sem fissura de palato não sindrômica (FL±P NS) é uma doença complexa que afeta 1:700 indivíduos no mundo. A busca das causas genéticas dessa malformação é dificultada pelo padrão multifatorial de herança e pela heterogeneidade genética, sendo que o gene IRF6 e a região 8q24 são os loci de associação mais corroborada. A estratificação populacional é um problema adicional a ser considerado em estudos de caso-controle na população brasileira. No intuito de caracterizar variáveis que possam interferir na busca dos fatores de risco, realizamos em um primeiro estudo uma avaliação epidemiológica de pacientes de cinco localidades do país (Santarém-PA, Barbalha-CE, Fortaleza-CE, Maceió-AL e Rio de Janeiro-RJ) . Este estudo revelou Barbalha como a região onde a genética desempenha papel mais determinante (herdabilidade = 85%; risco de recorrência = 2,2-2,8%); Maceió, por outro lado, foi a região de menor influência genética (herdabilidade = 45%; risco de recorrência = 0,6-0,7%). Ainda, a consangüinidade não mostrou um mecanismo importante para explicar estes resultados. Em um segundo estudo, realizamos a caracterização da ancestralidade da amostra, com o intuito de estabelecermos parâmetros para serem utilizados em futuros estudos de associação na nossa população. Para testarmos as nossas hipóteses realizamos um estudo de caso-controle com os SNPs mais corroborados nos dois loci em outras populações: rs642961 em um enhancer do gene IRF6 e rs987525 na região 8q24. Verificamos que quando realizamos um teste de associação para os SNPs com correção para estrutura populacional obtivemos resultados consistentes com as estimativas de herdabilidade, uma vez que Barbalha foi a única região de associação positiva para os SNPs. Apesar de estes SNPs terem sido estudados em outras populações, este é o primeiro relato de associação destes SNPs na população brasileira. Ainda, o estudo molecular revelou a importância da caracterização da estrutura populacional por meio de marcadores informativos de ancestralidade em estudos de caso-controle na nossa população, uma vez que resultados diferentes puderam ser observados em análise assumindo ausência de estratificação. Este trabalho fornece importantes bases para a identificação de novos genes de predisposição às FL±P NS na população brasileira, pois permite um direcionamento para as populações de maior contribuição genética nas abordagens que virão a ser realizadas. / Nonsyndromic cleft lip with or without cleft palate (NS CL±P) is a complex disease with worldwide incidence estimated as 1:700. The multifactorial model of inheritance and the genetic heterogeneity difficult the search for the genetic causes of NS CL±P, and, of all loci, IRF6 gene and 8q24 gene desert are the two most associated. The population stratification constitutes an additional problem to be considered in case-control studies in Brazil. In order to identify the factors that may interfere in the hunting of risk factors, we carried out, in a first moment, an epidemiologic evaluation of patients from five locations in Brazil (Santarém-PA, Barbalha-CE, Fortaleza-CE, Maceió-AL and Rio de Janeiro-RJ). This study put Barbalha as the region where genetic factors play the more determinant role (heritability = 85%; recurrence risk = 2.2-2.8%); Maceió, on the other hand, was the region of less genetic contribution to the disease (heritability = 45%; recurrence risk = 0.6-0.7%). In addition, consanguinity did not appear to influence these results. In a second study, we characterized the sample ancestry, in order to establish parameters for future association studies in our population. To test our hypothesis, we carried out a case-control study with the SNPs which are the most corroborated in other populations: rs642961 (in an IRF6 enhancer), and rs987525 (in 8q24). We verified that, when a structured association test was performed, we obtained results that are consistent with heritability estimates, since Barbalha was the only region with positive association for both SNPs. This was the first time that a positive association for these markers was reported in a Brazilian population. In addition, the molecular analysis evidenced the importance of an individual characterization with ancestry informative markers when performing a case-control study in this population, since different results were obtained from the analyses assuming no stratification and correcting its effect. This study provides important bases for the identification of new susceptibility variants to NS CL±P in Brazilian population, since targeting in the populations of highest genetic contribution to the disease will be possible in the forthcoming studies, increasing the power of the study.