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PubMed1997

Population-based family study designs: an interdisciplinary research framework for genetic epidemiology.

Most complex traits such as cancer and coronary heart diseases are attributed either to heritable factors or to environmental factors or to both. Dissecting the genetic and environmental etiology of complex traits thus requires an interdisciplinary research strategy. Genetic studies generally involve families and investigate familial aggregations of traits, segregation of major disease genes, and locations of disease genes on the human genome, the latter of which can be identified via linkage analysis. Epidemiologic studies often use population-based case-control studies to establish the role of specific environmental factors. Integrating both objectives, genetic epidemiology is to assess the associations of environmental factors with disease status, to quantify the aggregation of cases within families, to characterize putative disease genes via segregation analysis, and to localize disease genes via linkage analysis with genetic markers. To accomplish these objectives through designed studies, we propose a class of population-based family study designs, which are formed by choosing among sampling designs at three stages. The objectives of sampling at these three stages are 1) combined aggregation and association analysis, 2) combined segregation, aggregation, and association analysis, and 3) combined linkage, segregation, aggregation, and association analysis. These designs form an interdisciplinary research framework for genetic epidemiology. Our preliminary exploration of this framework and related analytic methods indicates that population-based family study designs retain the efficiency of linkage analysis for localizing disease genes without losing the property of being population-based, and they will therefore allow an assessment of a joint contribution of genetic and environmental factors to complex traits.

Case-Control Studies↗
PubMed2006

Mitochondrial DNA involvement in human longevity.

The main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future.

Cell Nucleus↗
PubMed2003

A genome-wide scan using tree-based association analysis for candidate loci related to fasting plasma glucose levels.

BACKGROUND: In the analysis of complex traits such as fasting plasma glucose levels, researchers often adjust the trait for some important covariates before assessing gene susceptibility, and may at times encounter confounding among the covariates and the susceptible genes. Previously, the tree-based method has been employed to accommodate the heterogeneity in complex traits. In this study, we performed a genome-wide screen on fasting glucose levels in the offspring generation of the Framingham Heart Study provided by the Genetic Analysis Workshop 13. We defined one quantitative trait and converted it to a dichotomous trait based on a predetermined cut-off value, and performed association analyses using regression and classification trees for the two traits, respectively. A marker was interpreted as positive if at least one of its alleles exhibited association in both analyses. Our purpose was to identify candidate genes susceptible to fasting glucose levels in the presence of other covariates. The covariates entered in the analysis including sex, body mass index, and lipids (total plasma cholesterol, high density lipoprotein cholesterol, and triglycerides) of the subjects, and those of their parents. RESULTS: Four out of seven positive regions in chromosomes 1, 2, 6, 11, 16, 18, and 19 from our analyses harbored or were very close to previously reported diabetes related genes or potential candidate genes. CONCLUSION: This screen method that employed tree-based association showed promise for identifying candidate loci in the presence of covariates in genome scans for complex traits.

Adult Children↗
PubMed2006

Heterozygosities of 735 microsatellite markers and background linkage disequilibrium in the Korean population.

Suitability of a specific population for linkage disequilibrium mapping studies of complex traits may be assessed by investigating the background linkage disequilibrium (BLD). We are unaware of studies for quantifying the degree of BLD in the Korean population, although the population may be a good candidate for mapping of complex trait genes through whole-genome association studies. It is useful to investigate the properties of genetic isolates in East Asia and to compare them to genetic isolates in Europe. We analyzed the extent of BLD in the Korean population using 735 microsatellite markers and compared the results with the Icelander population, which is one of the European expanded genetic isolates. The Korean population exhibited a level of BLD comparable with the Icelander population. The inference of population structure using the model with admixture showed that each individual has allele copies originating from K populations in equal proportions. Therefore, we believe that factors other than genetic distance, such as recent admixture, have not contributed to the level of BLD. Our results showed that the Korean population, which is an expanded population with no evidence of admixture, has a BLD level comparable with the Icelander population. Therefore, the Korean population can be used for fine mapping of either complex traits or monogenic diseases.

Adult↗
PubMed2006

Epistasis between loci on chromosomes 2 and 6 influences human height.

CONTEXT: Human height is a typical and important complex trait, which is determined by both actions and interactions of multiple genes. Although an increasing number of genes or genomic regions have been discovered for their independent effects on height variation, no study has been performed to identify genes or loci that interact to control the trait. OBJECTIVE: This study aimed to search for potential genomic regions that harbor interactive genes underlying human height. METHODS: Here with a sample containing 3726 Caucasians, the largest one ever obtained from a single population of the same ethnicity among genetic linkage studies of human complex traits, we performed variance component linkage analyses of height based on a two-locus epistatic model. We examined pairwise genetic interaction among three regions, 9q22, 6p21, and 2q21, which achieved significant or suggestive linkage signals for height in our recent whole genome scan. RESULTS: Significant genetic interaction between 6p21 and 2q21 was detected, with 2q21 achieving a maximum LOD score of 3.21 (P = 0.0035) under the epistatic model, compared with a maximum LOD score of 1.63 under a two-locus additive model. Interestingly, 6p21 contains a cluster of candidate genes for skeletal growth, suggesting a mechanism whereby 2q21 regulates height through 6p21. CONCLUSION: By providing the first evidence for genetic interaction underlying human height variation, this study further delineated the genetic architecture of human height and contributed to the genetic dissection of human complex traits in general.

Adult↗
PubMed2006

Linkage analysis using co-phenotypes in the BRIGHT study reveals novel potential susceptibility loci for hypertension.

Identification of the genetic influences on human essential hypertension and other complex diseases has proved difficult, partly because of genetic heterogeneity. In many complex-trait resources, additional phenotypic data have been collected, allowing comorbid intermediary phenotypes to be used to characterize more genetically homogeneous subsets. The traditional approach to analyzing covariate-defined subsets has typically depended on researchers' previous expectations for definition of a comorbid subset and leads to smaller data sets, with a concomitant attrition in power. An alternative is to test for dependence between genetic sharing and covariates across the entire data set. This approach offers the advantage of exploiting the full data set and could be widely applied to complex-trait genome scans. However, existing maximum-likelihood methods can be prohibitively computationally expensive, especially since permutation is often required to determine significance. We developed a less computationally intensive score test and applied it to biometric and biochemical covariate data, from 2,044 sibling pairs with severe hypertension, collected by the British Genetics of Hypertension (BRIGHT) study. We found genomewide-significant evidence for linkage with hypertension and several related covariates. The strongest signals were with leaner-body-mass measures on chromosome 20q (maximum LOD = 4.24) and with parameters of renal function on chromosome 5p (maximum LOD = 3.71). After correction for the multiple traits and genetic locations studied, our global genomewide P value was .046. This is the first identity-by-descent regression analysis of hypertension to our knowledge, and it demonstrates the value of this approach for the incorporation of additional phenotypic information in genetic studies of complex traits.

Chromosome Mapping↗
PubMed2001

Phenotypes and genetic analysis of psychiatric and neuropsychiatric traits.

A workshop was held at Rockefeller University entitled "Phenotypes and Genetic Analysis of Complex Traits." The purpose of the workshop was to examine phenotype definition for complex traits, in particular, psychiatric and neuropsychiatric traits. An additional goal of the workshop was to examine statistical genetic approaches that specifically address the oligogenic nature of psychiatric traits. An overview of topics that were addressed and discussed at the workshop is presented in this article.

Animals↗
PubMed1993

Pedigree models for complex human traits involving the mitochondrial genome.

Recent biochemical and molecular-genetic discoveries concerning variations in human mtDNA have suggested a role for mtDNA mutations in a number of human traits and disorders. Although the importance of these discoveries cannot be emphasized enough, the complex natures of mitochondrial biogenesis, mutant mtDNA phenotype expression, and the maternal inheritance pattern exhibited by mtDNA transmission make it difficult to develop models that can be used routinely in pedigree analyses to quantify and test hypotheses about the role of mtDNA in the expression of a trait. In the present paper, we describe complexities inherent in mitochondrial biogenesis and genetic transmission and show how these complexities can be incorporated into appropriate mathematical models. We offer a variety of likelihood-based models which account for the complexities discussed. The derivation of our models is meant to stimulate the construction of statistical tests for putative mtDNA contribution to a trait. Results of simulation studies which make use of the proposed models are described. The results of the simulation studies suggest that, although pedigree models of mtDNA effects can be reliable, success in mapping chromosomal determinants of a trait does not preclude the possibility that mtDNA determinants exists for the trait as well. Shortcomings inherent in the proposed models are described in an effort to expose areas in need of additional research.

Computer Simulation↗
PubMed2006

Appropriate use of information on family history of disease in recruitment for linkage analysis studies.

When conducting genetic studies for complex traits, large samples are commonly required to detect any of the number of genes with relatively low effect thought to underly such traits. This is because, in contrast to monogenic diseases, complex traits typically result from a number of different genetic pathways (genetic heterogeneity) and any sample is likely to contain a considerable fraction of sporadic cases (phenocopies). Such samples are time-consuming and costly to recruit and analyse. Methods which might be used to decrease sample size include attempting to select families, with the aim of reducing genetic heterogeneity or phenocopy rate within the sample. Selecting cases with positive family history of disease should reduce the phenocopy rate, and this strategy has been employed in linkage studies of complex disease, although evaluations of such a strategy have been equivocal. This paper shows how identity by descent (IBD) distributions may be calculated for affected relative pairs recruited conditional on the affection status of a third relative. These distributions are then used to calculate expected power in affected sib and half-sib linkage studies when recruitment is conditional on family history of disease. We consider the proxy conditions of recruitment conditional on disease in an affected parent or third sibling with single-locus and additive multilocus genetic models. We show that while such selection strategies can reduce power if disease risk alleles are common and environmental heterogeneity low, under models more likely to underly common complex diseases power will generally be increased, and that this effect is greater as more loci are involved. Though the proxy cases studied are more extreme than a general strategy of asking potential recruits whether they have any family history of disease, these results suggest that conditional recruitment is more generally useful than previous studies have suggested.

Family Health↗
PubMed2005

Haplotypes produced from rare variants in the promoter and coding regions of angiotensinogen contribute to variation in angiotensinogen levels.

The most efficient study design to map genes underlying complex traits will be determined by assumptions about whether the genetic effects are likely to be due to relatively few common variants or multiple rare variants. To examine the possibility that rare variants may influence blood pressure, we sequenced a 6.8 kb region of the angiotensinogen (AGT) gene in 29 male Nigerians with high plasma AGT levels and 28 with low levels. The frequency of haplotypes produced from rare variants in the promoter and coding regions was significantly different between the two groups, and it is unlikely that this difference was due to the manner in which the rare variants were selected. Further analysis suggested that most of the haplotypes produced by these rare variants are found on a haplotype background created by three common SNPs. Our study confirms in an additional trait that rare variants can influence the distribution of complex traits; whether these variants can be captured by common SNPs or haplotypes requires further investigation.

Angiotensinogen↗
PubMed2006

Role of the IBD5 susceptibility locus in the inflammatory bowel diseases.

The field of inflammatory bowel disease genetics plays a leading role in the genetics of complex traits. One of the first genetic loci for a complex trait to be identified by genome-wide linkage scans and confirmed by multiple studies was IBD1 for Crohn's disease. Shortly after this initial success, a second susceptibility locus, the IBD5 risk haplotype, was discovered and unequivocally replicated. In this review, we examine the genetics and potential functional implications of the IBD5 locus on disease susceptibility, prognosis, classification, and treatment. In addition, we discuss the challenges faced when the region identified by association contains multiple genes that are not easily separated by recombination-the primary tool of the human geneticist.

Chromosomes, Human, Pair 5↗
PubMed2026

Loss, persistence and reversal of phenotypic traits.

The irreversibility of complex trait loss has long been a tenet of evolutionary biology. However, this idea is increasingly at odds with the numerous documented exceptions across the Tree of Life. We synthesise this growing body of evidence across a diverse array of taxa and traits, exploring the evolutionary conditions that enable evolutionary reversal. By integrating macroevolutionary, genetic, and developmental information, we argue that trait reversal is commonly fostered by some form of persistence in the generative developmental pathway of the lost trait. We identify three overarching modes of trait reversal and support them with multiple case studies: by pleiotropy (the involvement of the same generative components in other traits and/or functions), by plasticity (environment-dependent expression of the trait) and by hemiplasy (persistence in another lineage, followed by reticulate evolution). We also examine important affinities between trait reversal and evolutionary novelties, undermining a neat distinction between what is old and what is new in evolution. This survey may provide a useful framework for future explorations of the developmental mechanisms underlying these still overlooked macroevolutionary dynamics.

Phenotype↗
PubMed2002

In silico discovery of gene-coding variants in murine quantitative trait loci using strain-specific genome sequence databases.

BACKGROUND: The identification of genes underlying complex traits has been aided by quantitative trait locus (QTL) mapping approaches, which in turn have benefited from advances in mammalian genome research. Most recently, whole-genome draft sequences and assemblies have been generated for mouse strains that have been used for a large fraction of QTL mapping studies. Here we show how such strain-specific mouse genome sequence databases can be used as part of a high-throughput pipeline for the in silico discovery of gene-coding variations within murine QTLs. As a test of this approach we focused on two QTLs on mouse chromosomes 1 and 13 that are involved in physical dependence on alcohol. RESULTS: Interstrain alignment of sequences derived from the relevant mouse strain genome sequence databases for 199 QTL-localized genes spanning 210,020 base-pairs of coding sequence identified 21 genes with different coding sequences for the progenitor strains. Several of these genes, including four that exhibit strong phenotypic links to chronic alcohol withdrawal, are promising candidates to underlie these QTLs. CONCLUSIONS: This approach has wide general utility, and should be applicable to any of the several hundred mouse QTLs, encompassing over 60 different complex traits, that have been identified using strains for which relatively complete genome sequences are available.

Alcohol Withdrawal Seizures↗
PubMed2006

Pleiotropic fitness effects of the Tre1-Gr5a region in Drosophila melanogaster.

The abundance of transposable elements and DNA repeat sequences in mammalian genomes raises the question of whether such insertions represent passive evolutionary baggage or may influence the expression of complex traits. We addressed this question in Drosophila melanogaster, in which the effects of single transposable elements on complex traits can be assessed in genetically identical individuals reared in controlled environments. Here we demonstrate that single P-element insertions in the intergenic region between the gustatory receptor 5a (Gr5a, also known as Tre) and trapped in endoderm 1 (Tre1), which encodes an orphan receptor, exert complex pleiotropic effects on fitness traits, including selective nutrient intake, life span, and resistance to starvation and heat stress. Mutations in this region interact epistatically with downstream components of the insulin signaling pathway. Transposon-induced sex-specific and sex-antagonistic effects further accentuate the complex influences that intergenic transposable elements can contribute to quantitative trait phenotypes.

Animals↗
PubMed2004

Evolution of a complex coevolved trait: active pollination in a genus of fig wasps.

Only three insect lineages have evolved complex active pollination behaviour and only fig wasps (Agaonidae) have also reverted from active to passive pollination. Previously, it was assumed that there was a single origin of active pollination in fig wasps, followed by one independent loss in each of five genera. We show here that there have been three to six changes in pollination behaviour within just one genus (Pleistodontes). The results suggest multiple gains of active pollination in fig wasps, but are sensitive to assumptions about the relative costs of gaining and losing this complex behaviour. In addition, previous comparative studies at higher taxonomic levels have reported correlated evolution between active pollination in wasps and low anther/ovule ratios in figs. We report that changes in pollination behaviour between congeneric species correlate perfectly with changes in anther/ovule ratios in the host figs, showing no phylogenetic inertia in coadaptation at the species level.

Animals↗
PubMed2005

Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22.

Bone mineral density (BMD) is a complex trait with a strong genetic component and an important predictor of osteoporotic fracture risk. Here we report the use of a cross-species strategy to identify genes that regulate BMD, proceeding from quantitative trait mapping in mice to association mapping of the syntenic region in the human genome. We identified a quantitative trait locus (QTL) on the mouse X-chromosome for post-maturity change in spine BMD in a cross of SAMP6 and AKR/J mice and conducted association mapping of the syntenic region on human chromosome Xp22. We studied 76 single nucleotide polymorphisms (SNP) from the human region in two sets of DNA pools prepared from individuals with lumbar spine-BMD (LS-BMD) values falling into the top and bottom 13th percentiles of a population-based study of 3100 post-menopausal women. This procedure identified a region of significant association for two adjacent SNP (rs234494 and rs234495) within the Xp22 locus (P<0.001). Individual genotyping for rs234494 in the BMD pools confirmed the presence of an association for alleles (P=0.018) and genotypes (P=0.008). Analysis of rs234494 and rs234495 in 1053 women derived from the same population who were not selected for BMD values showed an association with LS-BMD for rs234495 (P=0.01) and for haplotypes defined by both SNP (P=0.002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach.

Absorptiometry, Photon↗
PubMed2002

Candidate-gene approaches for studying complex genetic traits: practical considerations.

Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These challenges have led to pessimism about the candidate-gene approach and about the genetic analysis of complex diseases in general. We believe that these criticisms can be usefully countered with an appeal to the principles of epidemiological investigation.

Animals↗
PubMed2004

A statistical model for functional mapping of quantitative trait loci regulating drug response.

Differential drug response, that is, pharmacodynamics, is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. Genetic mapping has proven to be a powerful tool for detecting and identifying specific genes affecting complex traits, that is, quantitative trait loci (QTL), based on polymorphic markers. In this article, we present a novel statistical model for genetic mapping of QTL governing pharmacodynamic processes. In principle, this model is a combination of functional mapping proposed to map function-valued traits and linkage disequilibrium mapping designed to provide high-resolution mapping of QTL by making use of recombination events created at a historic time. We implement a closed-form solution for the Expectation-Maximization algorithm to estimate the population genetic parameters of QTL and the simplex algorithm to estimate the curve parameters describing the pharmacodynamic changes of different QTL genotypes in response to drug dose or concentrations. Extensive simulations are performed to investigate the statistical properties of our model. The implications of our model in pharmacogenetic and pharmacogenomic research are discussed.

Algorithms↗