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Human Heredity

Gaël Nicolas, Camille Charbonnier, Dominique Campion
Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player...
December 22, 2016: Human Heredity
Andreas Kitsche, Christian Ritz, Ludwig A Hothorn
OBJECTIVE: In this study, we present a simultaneous inference procedure as a unified analysis framework for genetic association studies. METHODS: The method is based on the formulation of multiple marginal models that reflect different modes of inheritance. The basic advantage of this methodology is that no explicit formulation of the correlation between the test statistics is required. Moreover, the genotype scores are considered as a quantitative explanatory variable, i...
December 22, 2016: Human Heredity
Chen Lu, George T O'Connor, Josée Dupuis, Eric D Kolaczyk
OBJECTIVE: Penalized regression has been successfully applied in genome-wide association studies. While meta-analysis is often conducted to increase power and protect patients' confidentiality, methods for meta-analyzing results of penalized regression in multi-cohort setting are still under development. METHODS: We propose to use a data-splitting method to obtain valid p values (or equivalently, coefficient estimates and standard errors) for meta-analysis across multiple cohorts...
December 22, 2016: Human Heredity
Wei Vivian Zhuang, Joanne M Murabito, Kathryn L Lunetta
BACKGROUND: In longitudinal epidemiological studies there may be individuals with rich phenotype data who die or are lost to follow-up before providing DNA for genetic studies. Often, the genotypic and phenotypic data of the relatives are available. Two strategies for analyzing the incomplete data are to exclude ungenotyped subjects from analysis (the complete-case method, CC) and to include phenotyped but ungenotyped individuals in analysis by using relatives' genotypes for genotype imputation (GI)...
August 31, 2016: Human Heredity
Emily Slade, Peter Kraft
OBJECTIVE: The association between DNA methylation and a trait of interest may depend on an environmental exposure, and incorrectly accounting for this dependence can lead to a reduction in power of the standard tests used in epigenome-wide association studies. We present the M-ME test to jointly test for the main effect of DNA methylation and methylation-environment interaction. METHODS: Through simulation, we compare the power and type 1 error of the M-ME test to a standard marginal test (M test) and a standard interaction test (ME test) under 1,800 different underlying models...
August 5, 2016: Human Heredity
Alexandre Bureau, Jordie Croteau
OBJECTIVES: To investigate the conditions and analysis strategies required so that endophenotypes related to a disease help discover genetic variants involved in the disease. METHODS: The association with disease susceptibility variants is examined as a function of the relationships between disease status, endophenotype values and the genotype at another disease or endophenotype susceptibility locus assumed to be previously known, using approximate linear models of allele frequencies as a function of these variables and simulations in the context of family studies when the endophenotype is dichotomous...
July 30, 2016: Human Heredity
Stacey Knight, Arthur T Maness, Sue M Dintelman, Benjamin D Horne
BACKGROUND: Many landmark genetic breakthroughs, including the recent discovery of PCSK-9 inhibitor drugs, were accomplished with substantial contributions from evaluation of pedigrees. Finding and ascertaining high-value pedigrees is not trivial and requires considerable time and cost. Here, we describe the creation of the Intermountain Genealogy Registry for use in studying the genetics of cardiovascular and other diseases. METHODS: Using publicly available pedigree records and probabilistic linkage techniques, we created a genealogy of ≈23 million records that we linked to 3...
July 16, 2016: Human Heredity
Weiqiang Zhou, Ben Sherwood, Hongkai Ji
Technological advances have led to an explosive growth of high-throughput functional genomic data. Exploiting the correlation among different data types, it is possible to predict one functional genomic data type from other data types. Prediction tools are valuable in understanding the relationship among different functional genomic signals. They also provide a cost-efficient solution to inferring the unknown functional genomic profiles when experimental data are unavailable due to resource or technological constraints...
2016: Human Heredity
(no author information available yet)
No abstract text is available yet for this article.
2016: Human Heredity
Xing Hua, James J Goedert, Maria Teresa Landi, Jianxin Shi
OBJECTIVES: Host genetics have been recently reported to affect human microbiome composition. We previously developed a statistical framework, microbiomeGWAS, to identify host genetic variants associated with microbiome composition by testing a distance matrix. However, statistical power depends on the choice of a microbiome distance matrix. To achieve more robust statistical power, we aim to extend microbiomeGWAS to test the association with many distance matrices, which are defined based on multilevel taxa abundances and phylogenetic information...
2016: Human Heredity
Tarmo Äijö, Richard Bonneau
Thanks to the confluence of genomic technology and computational developments, the possibility of network inference methods that automatically learn large comprehensive models of cellular regulation is closer than ever. This perspective focuses on enumerating the elements of computational strategies that, when coupled to appropriate experimental designs, can lead to accurate large-scale models of chromatin state and transcriptional regulatory structure and dynamics. We highlight 4 research questions that require further investigation in order to make progress in network inference: (1) using overall constraints on network structure such as sparsity, (2) use of informative priors and data integration to constrain individual model parameters, (3) estimation of latent regulatory factor activity under varying cell conditions, and (4) new methods for learning and modeling regulatory factor interactions...
2016: Human Heredity
Xuexia Wang, Rui Xiao, Xiaofeng Zhu, Mingyao Li
A family-based study design is commonly used in gene mapping studies of complex human diseases. Most family-based studies use the transmission of alleles to assess evidence of association. It is generally believed that the transmission disequilibrium test (TDT) is robust against spurious association due to population stratification or admixture. While this is true when population stratification is due to discrete population structure, one should use the TDT-type methods with caution when they are applied to admixed populations in which population structure exists in local genomic regions...
2016: Human Heredity
(no author information available yet)
No abstract text is available yet for this article.
2016: Human Heredity
Zachary Zappala, Stephen B Montgomery
Whole-genome and exome sequencing in human populations has revealed the tolerance of each gene for loss-of-function variation. By understanding this tolerance, it has become increasingly possible to identify genes that would make safe therapeutic targets and to identify rare genetic risk factors and phenotypes at the scale of individual genomes. To date, the vast majority of surveyed loss-of-function variants are in protein-coding regions of the genome mainly due to the focus on these regions by exome-based sequencing projects and their relative ease of interpretability...
2016: Human Heredity
(no author information available yet)
No abstract text is available yet for this article.
March 11, 2015: Human Heredity
(no author information available yet)
No abstract text is available yet for this article.
2015: Human Heredity
Claire Dandine-Roulland, Hervé Perdry
We give a short but detailed review of the methods used to deal with linear mixed models (restricted likelihood, AIREML algorithm, best linear unbiased predictors, etc.), with a few original points. Then we describe three common applications of the linear mixed model in contemporary human genetics: association testing (pathways analysis or rare variants association tests), genomic heritability estimates, and correction for population stratification in genome-wide association studies. We also consider the performance of best linear unbiased predictors for prediction in this context, through a simulation study for rare variants in a short genomic region, and through a short theoretical development for genome-wide data...
2015: Human Heredity
Duo Jiang, Joelle Mbatchou, Mary Sara McPeek
Case-control genetic association analysis is an extremely common tool in human complex trait mapping. From a statistical point of view, the analysis of binary traits poses somewhat different challenges from the analysis of quantitative traits. Desirable features of a binary trait mapping approach would include (1) phenotype modeled as binary, with appropriate dependence between the mean and variance; (2) appropriate correction for relevant covariates; (3) appropriate correction for sample structure of various types, including related individuals, admixture and other types of population structure; (4) both fast and accurate computations; (5) robustness to ascertainment and other types of phenotype model misspecification, and (6) ability to leverage partially missing data to increase power...
2015: Human Heredity
Frank Dudbridge, Paul J Newcombe
OBJECTIVE: Gene scores are often used to model the combined effects of genetic variants. When variants are in linkage disequilibrium, it is common to prune all variants except the most strongly associated. This avoids duplicating information but discards information when variants have independent effects. However, joint modelling of correlated variants increases the sampling error in the gene score. In recent applications, joint modelling has offered only small improvements in accuracy over pruning...
2015: Human Heredity
Emmanuelle Génin, Françoise Clerget-Darpoux
Most studies on multifactorial diseases are performed under the assumption of a polygenic additive liability. In particular, missing heritability and individual risk scores are estimated under this model. In this paper, we use the example of diabetes to highlight the pitfalls of relying on such a model, when there are reasons to suspect etiological heterogeneity and/or departure from the hypotheses on the environmental factor effects.
2015: Human Heredity
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