Rare disease variants are receiving increasing importance in the past few years as the potential cause for many complex diseases, after the common disease variants failed to explain a large part of the missing heritability. With the advancement in sequencing techniques as well as computational capabilities, statistical methodology for analyzing rare variants is now a hot topic, especially in case-control association studies. In this thesis, we initially present two related statistical methodologies designed for case-control studies to predict the number of common and rare variants in a particular genomic region underlying the complex disease. Genome-wide association studies are nowadays routinely performed to identify a few putative marker loci or a candidate region for further analysis. These methods are designed to work with SNP data on such a genomic region highlighted by GWAS studies for potential disease variants. The fundamental idea is to use Bayesian methodology to obtain bivariate posterior distributions on counts of common and rare variants. While the first method uses randomly generated (minimal) ancestral recombination graphs, the second method uses ensemble clustering method to explore the space of genealogical trees that represent the inherent structure in the test subjects. In contrast to the aforesaid methods which work with SNP data, the third chapter deals with next-generation sequencing data to detect the presence of rare variants in a genomic region. We present a non-parametric statistical methodology for rare variant association testing, using the well-known Kolmogorov-Smirnov framework adapted for genetic data. it is a fast, model-free robust statistic, designed for situations where both deleterious and protective variants are present. It is also unique in utilizing the variant locations in the test statistic.

During the last two decades, genotyping technology has advanced rapidly, which enabled the tremendous success of genome-wide association studies (GWAS) in the search of disease susceptibility loci (DSLs). However, only a small fraction of the overall predicted heritability can be explained by the DSLs discovered. One possible explanation for this ”missing heritability” phenomenon is that many causal variants are rare. The recent development of high-throughput next-generation sequencing (NGS) technology provides the instrument to look closely at these rare variants with precision and efficiency. However, new approaches for both the storage and analysis of sequencing data are in imminent needs. In this thesis, we introduce three methods that could be utilized in the management and analysis of sequencing data. In Chapter 1, we propose a novel and simple algorithm for compressing sequencing data that leverages on the scarcity of rare variant data, which enables the storage and analysis of sequencing data efficiently in current hardware environment. We also provide a C++ implementation that supports direct and parallel loading of the compressed format without requiring extra time for decompression. Chapter 2 and 3 focus on the association analysis of sequencing data in population-based design. In Chapter 2, we present a statistical methodology that allows the identification of genetic outliers to obtain a genetically homogeneous subpopulation, which reduces the false positives due to population substructure. Our approach is computationally efficient that can be applied to all the genetic loci in the data and does not require pruning of variants in linkage disequilibrium (LD). In Chapter 3, we propose a general analysis framework in which thousands of genetic loci can be tested simultaneously for association with complex phenotypes. The approach is built on spatial-clustering methodology, assuming that genetic loci that are associated with the target phenotype cluster in certain genomic regions. In contrast to standard methodology for multi-loci analysis, which has focused on the dimension reduction of data, the proposed approach profits from the availability of large numbers of genetic loci. Thus it will be especially relevant for whole-genome sequencing studies which commonly record several thousand loci per gene.

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.

Statistical association tests of quantitative traits have been widely used in the past decade, to locate loci associated with a disease trait. For instance, Genome Wide Association Studies (GWAS) have led to tremendous success in finding susceptible genes or associated loci. However, most of the past studies were based on unrelated samples focusing on quantitative or qualitative traits. The analysis of polychotomous traits in family samples is very challenging. This dissertation describes three projects related to methods to conduct association tests beyond continuous traits, such as multinomial traits, bivariate traits, and tests involving haplotypes. The first project focuses on developing a statistical approach to test the association between common or low-frequency variants with a multinomial trait in family samples. It is an important issue because there is no computer efficient software available for this type of question. We employ Laplace approximation in conjunction with an efficient grid-search strategy to obtain an approximate maximum log-likelihood function and the Maximum Likelihood Estimate (MLE) of the variance component. We also successfully incorporate the kinship matrix to adjust for the familial correlation, based on a regression framework. Extensive simulation studies are performed to evaluate the type-I error rate and power in scenarios with causal variant with different Minor Allele Frequency (MAF). In the second project, we propose an approach to test the association between a genetic variant and a bivariate trait arising from a combination of a quantitative and a binary trait in family samples, based on Extended Generalized Estimating Equations (EGEE). Multiple phenotype-genotype association tests are often reduced to univariate tests, decreasing efficiency and power. Our approach is shown to be much more powerful and efficient than univariate association tests adjusted for multiple testing. The third project involves the development of a general framework for meta-analysis of haplotype association tests, applicable to both unrelated and family samples. Although meta-analysis has been widely used in single-variant and gene-based tests, there are few existing methods to meta-analyze haplotype association tests. A predominant advantage of our novel approach is that it accommodates cohort-specific haplotypes as well as haplotypes common to all cohorts. The cohort participants may be either related or unrelated. Our approach consists of two stages: in the first stage, each cohort performs a haplotype association test, reports the estimates of effect size, variance, haplotypes, and their frequency. In the second stage, a generalized least square method is applied to combine the results of all the cohorts into one vector of meta-analysis coefficients. Our approach is shown to have the correct type-I error rate in scenarios with different between and within cohort variation. We also present an application to exome-chip data from a large consortium. Through the three projects, we are able to tackle the problem of conducting association tests for non-continuous traits in family samples. All the approaches achieve the correct type-I error rate and are computationally efficient. We hope these approaches will not only facilitate analyses of categorical traits in family samples, but will also provide a basis for future methodological development of statistical approaches for non-continuous traits.

Introdução: Os transtornos de ansiedade (TA) são prevalentes na infância e na adolescência e geram prejuízos significativos, podendo persistir na vida adulta. Os traços de personalidade e temperamento associados à ansiedade, como o comportamento inibido (CI) e a evitação de danos, também devem ser considerados. O neurotransmissor serotonina possui um papel crítico no desenvolvimento e na plasticidade do encéfalo. O gene do seu transportador (5-HTT) é um forte candidato para estudos de associação genéticos e psiquiátricos. O polimorfismo na região promotora do gene do 5-HTT (5-HTTLPR) é funcional e, portanto, de relevância para estudos de associação na psiquiatria. Objetivos: Investigar a associação entre o 5-HTTLPR, através da sua classificação bialélica e trialélica, e os TA e fenótipos relacionados à ansiedade (CI e evitação de danos), em uma amostra de adolescentes ansiosos e não-ansiosos e seus familiares. Metodologia: Um total de 510 indivíduos participou do estudo. Os participantes foram 225 adolescentes (129 casos e 96 controles para TA) e seus familiares biológicos (194 mães, 63 pais e 22 irmãos). Foi realizado o diagnóstico psiquiátrico através de entrevista clínica e do Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version Diagnostic Interview (K-SADS-PL). A escala Temperament and Character Inventory (TCI) e uma adaptação da escala Retrospective Self-report Scale of Behavioral Inhibition foram usadas para mensurar a evitação de danos e o comportamento inibido, respectivamente. As análises moleculares resultaram da extração de DNA da amostra de saliva dos adolescentes e seus familiares, seguida de amplificação do DNA por PCR e digestão enzimática com enzima MspI. Os genótipos foram agrupados pelo nível de expressividade: baixo (SS, LGS, LGLG); intermediário (LALG, LAS) e alto (LALA). A análise estatística foi realizada com o software PLINK e nível de significância α < 0.05. Resultados: Não foi encontrada associação entre o 5-HTTLPR, considerando a classificação bialélica e trialélica, e os transtornos de ansiedade, comportamento inibido e a evitação, tanto no caso-controle quanto no estudo de trios. Conclusões: Nossos resultados não sugerem a presença de associação entre o 5-HTTLPR e os transtornos de ansiedade e seus fenótipos relacionados (comportamento inibido e evitação de danos) em adolescentes. Diante de resultados controversos descritos na literatura, estudos de meta-análises podem ser necessários para auxiliar no esclarecimento sobre essa questão. / Introduction: Anxiety disorders (AD) are prevalent in childhood and adolescence and results in significant impairments. It usually persists into adulthood. Anxiety traits such as behavioral inhibition and harm avoidance may also be considered. The serotonin neurotransmitter plays an important role in the development and the plasticity of the brain. The serotonin transporter gene (5-HTT) is considered a strong candidate and the Serotonin Transporter Gene-linked Polymorphic Region (5-HTTLPR) functional and, therefore, relevant in studies concerning the association between genetic and psychiatric disorders. Objectives: To investigate the association between 5-HTTLPR (biallelic and triallelic classification) and AD and anxiety related phenotypes (behavioral inhibition and harm avoidance) in a sample of adolescents and their families. Methodology: A total of 510 subjects participated in this study. Participants were 225 adolescents (129 anxiety cases and 96 community controls) and their biological families (194 mothers, 66 fathers and 22 siblings). We assessed psychiatric diagnosis throughout a clinical interview and using the Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version Diagnostic Interview (K-SADS-PL). The Temperament and Character Inventory (TCI) and an adaptation of the Resnick Behavioral Inhibition Scale were used in order to measure harm avoidance and behavioral inhibition, respectively. The molecular analysis resulted in the extraction of DNA from saliva sample of the adolescents and their families, followed by DNA amplification by PCR and enzymatic digestion with the MspI. The genotypes were grouped by level of expression: low (SS, LGS, LGLG); intermediated (LALG, LAS) and high (LALA). Statistical analysis was performed with the software PLINK, with the significance level of α < 0.05. Results: No association was found between 5-HTTLPR, considering the biallelic or triallelic analysis, and anxiety disorders, behavioral inhibition and harm avoidance in both case-control and trios studies. Conclusion: Our results do not support a major role of 5-HTTLPR in anxiety disorders and anxiety-related phenotypes (behavioral inhibition and harm avoidance) in adolescents. In the face of mixed results, further investigations and meta-analytic studies are needed in order to clarify this research question.

Introdução: Os transtornos de ansiedade (TA) são prevalentes na infância e na adolescência e geram prejuízos significativos, podendo persistir na vida adulta. Os traços de personalidade e temperamento associados à ansiedade, como o comportamento inibido (CI) e a evitação de danos, também devem ser considerados. O neurotransmissor serotonina possui um papel crítico no desenvolvimento e na plasticidade do encéfalo. O gene do seu transportador (5-HTT) é um forte candidato para estudos de associação genéticos e psiquiátricos. O polimorfismo na região promotora do gene do 5-HTT (5-HTTLPR) é funcional e, portanto, de relevância para estudos de associação na psiquiatria. Objetivos: Investigar a associação entre o 5-HTTLPR, através da sua classificação bialélica e trialélica, e os TA e fenótipos relacionados à ansiedade (CI e evitação de danos), em uma amostra de adolescentes ansiosos e não-ansiosos e seus familiares. Metodologia: Um total de 510 indivíduos participou do estudo. Os participantes foram 225 adolescentes (129 casos e 96 controles para TA) e seus familiares biológicos (194 mães, 63 pais e 22 irmãos). Foi realizado o diagnóstico psiquiátrico através de entrevista clínica e do Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version Diagnostic Interview (K-SADS-PL). A escala Temperament and Character Inventory (TCI) e uma adaptação da escala Retrospective Self-report Scale of Behavioral Inhibition foram usadas para mensurar a evitação de danos e o comportamento inibido, respectivamente. As análises moleculares resultaram da extração de DNA da amostra de saliva dos adolescentes e seus familiares, seguida de amplificação do DNA por PCR e digestão enzimática com enzima MspI. Os genótipos foram agrupados pelo nível de expressividade: baixo (SS, LGS, LGLG); intermediário (LALG, LAS) e alto (LALA). A análise estatística foi realizada com o software PLINK e nível de significância α < 0.05. Resultados: Não foi encontrada associação entre o 5-HTTLPR, considerando a classificação bialélica e trialélica, e os transtornos de ansiedade, comportamento inibido e a evitação, tanto no caso-controle quanto no estudo de trios. Conclusões: Nossos resultados não sugerem a presença de associação entre o 5-HTTLPR e os transtornos de ansiedade e seus fenótipos relacionados (comportamento inibido e evitação de danos) em adolescentes. Diante de resultados controversos descritos na literatura, estudos de meta-análises podem ser necessários para auxiliar no esclarecimento sobre essa questão. / Introduction: Anxiety disorders (AD) are prevalent in childhood and adolescence and results in significant impairments. It usually persists into adulthood. Anxiety traits such as behavioral inhibition and harm avoidance may also be considered. The serotonin neurotransmitter plays an important role in the development and the plasticity of the brain. The serotonin transporter gene (5-HTT) is considered a strong candidate and the Serotonin Transporter Gene-linked Polymorphic Region (5-HTTLPR) functional and, therefore, relevant in studies concerning the association between genetic and psychiatric disorders. Objectives: To investigate the association between 5-HTTLPR (biallelic and triallelic classification) and AD and anxiety related phenotypes (behavioral inhibition and harm avoidance) in a sample of adolescents and their families. Methodology: A total of 510 subjects participated in this study. Participants were 225 adolescents (129 anxiety cases and 96 community controls) and their biological families (194 mothers, 66 fathers and 22 siblings). We assessed psychiatric diagnosis throughout a clinical interview and using the Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version Diagnostic Interview (K-SADS-PL). The Temperament and Character Inventory (TCI) and an adaptation of the Resnick Behavioral Inhibition Scale were used in order to measure harm avoidance and behavioral inhibition, respectively. The molecular analysis resulted in the extraction of DNA from saliva sample of the adolescents and their families, followed by DNA amplification by PCR and enzymatic digestion with the MspI. The genotypes were grouped by level of expression: low (SS, LGS, LGLG); intermediated (LALG, LAS) and high (LALA). Statistical analysis was performed with the software PLINK, with the significance level of α < 0.05. Results: No association was found between 5-HTTLPR, considering the biallelic or triallelic analysis, and anxiety disorders, behavioral inhibition and harm avoidance in both case-control and trios studies. Conclusion: Our results do not support a major role of 5-HTTLPR in anxiety disorders and anxiety-related phenotypes (behavioral inhibition and harm avoidance) in adolescents. In the face of mixed results, further investigations and meta-analytic studies are needed in order to clarify this research question.

Introdução: Os transtornos de ansiedade (TA) são prevalentes na infância e na adolescência e geram prejuízos significativos, podendo persistir na vida adulta. Os traços de personalidade e temperamento associados à ansiedade, como o comportamento inibido (CI) e a evitação de danos, também devem ser considerados. O neurotransmissor serotonina possui um papel crítico no desenvolvimento e na plasticidade do encéfalo. O gene do seu transportador (5-HTT) é um forte candidato para estudos de associação genéticos e psiquiátricos. O polimorfismo na região promotora do gene do 5-HTT (5-HTTLPR) é funcional e, portanto, de relevância para estudos de associação na psiquiatria. Objetivos: Investigar a associação entre o 5-HTTLPR, através da sua classificação bialélica e trialélica, e os TA e fenótipos relacionados à ansiedade (CI e evitação de danos), em uma amostra de adolescentes ansiosos e não-ansiosos e seus familiares. Metodologia: Um total de 510 indivíduos participou do estudo. Os participantes foram 225 adolescentes (129 casos e 96 controles para TA) e seus familiares biológicos (194 mães, 63 pais e 22 irmãos). Foi realizado o diagnóstico psiquiátrico através de entrevista clínica e do Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version Diagnostic Interview (K-SADS-PL). A escala Temperament and Character Inventory (TCI) e uma adaptação da escala Retrospective Self-report Scale of Behavioral Inhibition foram usadas para mensurar a evitação de danos e o comportamento inibido, respectivamente. As análises moleculares resultaram da extração de DNA da amostra de saliva dos adolescentes e seus familiares, seguida de amplificação do DNA por PCR e digestão enzimática com enzima MspI. Os genótipos foram agrupados pelo nível de expressividade: baixo (SS, LGS, LGLG); intermediário (LALG, LAS) e alto (LALA). A análise estatística foi realizada com o software PLINK e nível de significância α < 0.05. Resultados: Não foi encontrada associação entre o 5-HTTLPR, considerando a classificação bialélica e trialélica, e os transtornos de ansiedade, comportamento inibido e a evitação, tanto no caso-controle quanto no estudo de trios. Conclusões: Nossos resultados não sugerem a presença de associação entre o 5-HTTLPR e os transtornos de ansiedade e seus fenótipos relacionados (comportamento inibido e evitação de danos) em adolescentes. Diante de resultados controversos descritos na literatura, estudos de meta-análises podem ser necessários para auxiliar no esclarecimento sobre essa questão. / Introduction: Anxiety disorders (AD) are prevalent in childhood and adolescence and results in significant impairments. It usually persists into adulthood. Anxiety traits such as behavioral inhibition and harm avoidance may also be considered. The serotonin neurotransmitter plays an important role in the development and the plasticity of the brain. The serotonin transporter gene (5-HTT) is considered a strong candidate and the Serotonin Transporter Gene-linked Polymorphic Region (5-HTTLPR) functional and, therefore, relevant in studies concerning the association between genetic and psychiatric disorders. Objectives: To investigate the association between 5-HTTLPR (biallelic and triallelic classification) and AD and anxiety related phenotypes (behavioral inhibition and harm avoidance) in a sample of adolescents and their families. Methodology: A total of 510 subjects participated in this study. Participants were 225 adolescents (129 anxiety cases and 96 community controls) and their biological families (194 mothers, 66 fathers and 22 siblings). We assessed psychiatric diagnosis throughout a clinical interview and using the Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version Diagnostic Interview (K-SADS-PL). The Temperament and Character Inventory (TCI) and an adaptation of the Resnick Behavioral Inhibition Scale were used in order to measure harm avoidance and behavioral inhibition, respectively. The molecular analysis resulted in the extraction of DNA from saliva sample of the adolescents and their families, followed by DNA amplification by PCR and enzymatic digestion with the MspI. The genotypes were grouped by level of expression: low (SS, LGS, LGLG); intermediated (LALG, LAS) and high (LALA). Statistical analysis was performed with the software PLINK, with the significance level of α < 0.05. Results: No association was found between 5-HTTLPR, considering the biallelic or triallelic analysis, and anxiety disorders, behavioral inhibition and harm avoidance in both case-control and trios studies. Conclusion: Our results do not support a major role of 5-HTTLPR in anxiety disorders and anxiety-related phenotypes (behavioral inhibition and harm avoidance) in adolescents. In the face of mixed results, further investigations and meta-analytic studies are needed in order to clarify this research question.

The current dissertation used a gene x environment (G x E) approach to examine the independent and interactive effects of specific genetic variants and participation in physical and cognitive/social activities (PA and CSA) on cognitive performance in 4,764 participants of the Health and Retirement Study. Using three-wave data, three sets of multi-level growth models were conducted to examine baseline, longitudinal, and interactive effects of genotype (i.e., ApoE, COMT, and BDNF) and CSA/PA on performance across five cognitive measures: immediate, delayed and total word recall, and serial 7s and backwards counting. At baseline, the ApoE ε4 allele predicted worse performance in all measures except backwards counting, and the BDNF Met allele predicted better recall scores. The effect of COMT genotype was not significant. Higher CSA/PA predicted better performance on almost all measures. One significant G x E interaction was found between COMT x CSA for backwards counting. Longitudinally, participation in CSA moderated the effect of time on word recall in the ApoE and BDNF models. These results support the idea that genetic and environmental factors are mechanisms of cognitive aging, but also exemplify the variability seen in genetic association studies. Further research is needed to translate such findings into clinically relevant criteria that can be used to identify individual susceptibility to cognitive decline.

Genetic heterogeneity, lifestyle factors, gene-gene or gene-environment interactions are the determinants of T2D which puts Hispanics and populations with African ancestry at higher risk of developing T2D. In this dissertation, the genetic associations of PPARGC1A polymorphisms with T2D and its related phenotypes (metabolic markers) in Haitian Americans (cases=110, controls=116), African Americans (cases=120, controls=124) and Cuban Americans (cases=160, controls=181) of South Florida were explored. Five single nucleotide polymorphisms of gene PPARGC1A were evaluated in each ethnicity for their disease association. In Haitian Americans, rs7656250 (OR= 0.22, pp=0.03) had significant protective association with T2D but had risk association in African Americans for rs7656250 (OR=1.02, p=0.96) and rs4235308 (OR=2.53, p=0.03). We found that in Haitian American females, both rs7656250 (OR=0.23, pp=0.03) had protective association with T2D. In African American females, rs7656250 (OR=1.14, p=0.78) had risk association whereas in males, it had significant protective effect (OR=0.37, p=0.04). However, the risk association exhibited by rs4235308 was stronger in African American females (OR=2.69, p=0.03) than males (OR=1.16, p=0.72). In Cuban Americans, only rs7656250 showed significant risk association with T2D (OR=6.87, p=0.02) which was stronger in females alone (OR=7.67, p=0.01). We also observed significant differences among correlations of PPARGC1A SNPs and T2D phenotypes. Positive correlation was observed for log Hs-CRP with rs3774907 (pp=0.03) in Cuban Americans respectively. Correlation of log A1C with rs7656250 (p=0.02) was positive in Cuban Americans while it was negative for rs3774907 in Haitian Americans (ppPPARGC1A correlations with T2D and its phenotypes among the three ethnicities studied (ii) the associations of PPARGC1A SNPs showed significant effect modification by sex. The findings suggest that variations in effects of PPARGC1A gene polymorphisms among three ethnicities and between sexes may have biomedical implications for the development of T2D as well as the phenotypes related to T2D.