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PubMed2005

Mapping determinants of human gene expression by regional and genome-wide association.

To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of approximately 1,000 expression phenotypes. In the present study, we carried out association analysis with dense sets of single-nucleotide polymorphism (SNP) markers from the International HapMap Project. For 374 phenotypes, the association study was performed with markers only from regions with strong linkage evidence; these regions all mapped close to the expressed gene. For a subset of 27 phenotypes, analysis of genome-wide association was performed with >770,000 markers. The association analysis with markers under the linkage peaks confirmed the linkage results and narrowed the candidate regulatory regions for many phenotypes with strong linkage evidence. The genome-wide association analysis yielded highly significant results that point to the same locations as the genome scans for about 50% of the phenotypes. For one candidate determinant, we carried out functional analyses and confirmed the variation in cis-acting regulatory activity. Our findings suggest that association studies with dense SNP maps will identify susceptibility loci or other determinants for some complex traits or diseases.

Alleles↗

PubMed1996

A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish.

The most characteristic features of bipolar affective disorder (manic-depressive illness) are episodes of mania (bipolar I, BPI) or hypomania (bipolar II, BPII) interspersed with periods of depression. Manic-depressive illness afflicts about one percent of the population, and if untreated, is associated with an approximately 20% risk of suicide. Twin, family and adoption studies provide compelling evidence for a partial genetic aetiology, but the mode(s) of inheritance has not been identified. Nonetheless, the majority of genetic linkage studies have assumed classical mendelian inheritance attributable to a single major gene. Although segregation analyses have yielded inconsistent results (with most studies rejecting a single locus inheritance model), the best single gene model is dominant inheritance if only BPI is considered. Reported linkages of bipolar affective disorder on chromosomes 11, 18, 21 and X have been difficult to substantiate, and additional studies are required for replication or exclusion of these regions. We now present the results of our genome-wide linkage analyses that provide evidence that regions on chromosomes 6, 13 and 15 harbour susceptibility loci for bipolar affective disorder, suggesting that bipolar affective disorder in the Old Order Amish is inherited as a complex trait.

Alleles↗

PubMed1997

Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome.

Using Down syndrome as a model for complex trait analysis, we sought to identify loci from chromosome 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. We generated low-copy-number transgenic mice, containing four different yeast artificial chromosomes (YACs) that together cover approximately 2 megabases (Mb) of contiguous DNA from 21q22.2. We subjected independent lines derived from each of these YAC transgenes to a series of behavioural and learning assays. Two of the four YACs caused defects in learning and memory in the transgenic animals, while the other two YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region contains the human homologue of a Drosophila gene, minibrain, and strongly implicates it in learning defects associated with Down syndrome.

Animals↗

PubMed1997

Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains.

Congenic breeding strategies are becoming increasingly important as a greater number of complex trait linkages are identified. Traditionally, the development of a congenic strain has been a time-consuming endeavour, requiring ten generations of backcrosses. The recent advent of a dense molecular genetic map of the mouse permits methods that can reduce the time needed for congenic-strain production by 18-24 months. We present a theoretical evaluation of marker-assisted congenic production and provide the empirical data that support it. We present this 'speed congenic' method in a user-friendly manner to encourage other investigators to pursue this or similar methods of congenic production.

Animals↗

PubMed1997

Demographic history and linkage disequilibrium in human populations.

In the human genome, linkage disequilibrium (LD)--the non-random association of alleles at chromosomal loci--has been studied mainly in regions surrounding disease genes on affected chromosomes. Consequently, little information is available on the distribution of LD across anonymous genomic regions in the general population. However, demographic history is expected to influence the extent of overall LD across the genome, so a population that has been of constant size will display higher levels of LD than a population that has expanded. In support of this, the extent of LD between anonymous loci on chromosome 4 in chimpanzees (as a model of a population of constant size) has been compared to that in Finns (as a model of an expanded population; refs 8,9) and found to exhibit more LD than in the latter population. In Europe, studies of mitochondrial (mt) DNA sequences have suggested that most populations have experienced expansion, whereas the Saami in northern Fenno-Scandinavia have been of constant size (Table 1). Thus, in northern Europe, populations with radically different demographic histories live in close geographic proximity to each other. We studied the allelic associations between anonymous microsatellite loci on the X chromosome in the Saami and neighbouring populations and found dramatically higher levels of LD in the Saami than in other populations in the region. This indicates that whereas recently expanded populations, such as the Finns, are well suited to map single disease genes affected by recent mutations, populations that have been of constant size, such as the Saami, may be much better suited to map genes for complex traits that are caused by older mutations.

Alleles↗

PubMed2004

Germline epimutation of MLH1 in individuals with multiple cancers.

Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. We hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. Here we report two individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lack evidence of genetic mutation in any mismatch repair gene but have had multiple primary tumors that show mismatch repair deficiency, and both meet clinical criteria for hereditary nonpolyposis colorectal cancer. The epimutation was also present in spermatozoa of one of the individuals, indicating a germline defect and the potential for transmission to offspring. Germline epimutation provides a mechanism for phenocopying of genetic disease. The mosaicism and nonmendelian inheritance that are characteristic of epigenetic states could produce patterns of disease risk that resemble those of polygenic or complex traits.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Assessing genetic contributions to phenotypic differences among 'racial' and 'ethnic' groups.

Descriptions of human genetic variation given thirty years ago have held up well, considering the substantial accrual of DNA sequence data in the interim. Most importantly, estimates of between-group genetic variation have remained relatively low. Despite the low average level of between-group variation, clusters recently inferred from multilocus genetic data coincide closely with groups defined by self-identified race or continental ancestry. This correspondence implies that genetic factors might contribute to unexplained between-group phenotypic variation. Current understanding of the contribution of genes to variation in most complex traits is limited, however. Under these circumstances, assumptions about genetic contributions to group differences are unfounded. In the absence of detailed understanding, 'racial' and 'ethnic' categories will remain useful in biomedical research. Further, we suggest approaches and guidelines for assessing the contribution of genetic factors to between-group phenotypic differences, including studies of candidate genes and analyses of recently admixed populations.

DNA↗

PubMed2005

Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease.

Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.

Animals↗

PubMed2005

Genomic screening and replication using the same data set in family-based association testing.

The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome-wide family-based association studies, using single SNPs or haplotypes, can identify associations that achieve genome-wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease-susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease-susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype-tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome-wide significance, as population-based designs do.

Asthma↗

PubMed2005

The origins and uses of mouse outbred stocks.

Outbred mouse stocks, often used in genetics, toxicology and pharmacology research, have been generated in rather haphazard ways. Understanding the characteristics of these stocks and their advantages and disadvantages is important for experimental design. In many studies these mice are used inappropriately, wasting animals' lives and resources on suboptimal experiments. Recently, however, researchers from the field of complex trait analysis have capitalized on the genetics of outbred stocks to refine the identification of quantitative trait loci. Here we assess the most widely used outbred stocks of mice and present guidelines for their use.

Animals↗

PubMed2006

Physiogenomic resources for rat models of heart, lung and blood disorders.

Cardiovascular disorders are influenced by genetic and environmental factors. The TIGR rodent expression web-based resource (TREX) contains over 2,200 microarray hybridizations, involving over 800 animals from 18 different rat strains. These strains comprise genetically diverse parental animals and a panel of chromosomal substitution strains derived by introgressing individual chromosomes from normotensive Brown Norway (BN/NHsdMcwi) rats into the background of Dahl salt sensitive (SS/JrHsdMcwi) rats. The profiles document gene-expression changes in both genders, four tissues (heart, lung, liver, kidney) and two environmental conditions (normoxia, hypoxia). This translates into almost 400 high-quality direct comparisons (not including replicates) and over 100,000 pairwise comparisons. As each individual chromosomal substitution strain represents on average less than a 5% change from the parental genome, consomic strains provide a useful mechanism to dissect complex traits and identify causative genes. We performed a variety of data-mining manipulations on the profiles and used complementary physiological data from the PhysGen resource to demonstrate how TREX can be used by the cardiovascular community for hypothesis generation.

Animals↗

PubMed2005

A high-resolution survey of deletion polymorphism in the human genome.

Recent work has shown that copy number polymorphism is an important class of genetic variation in human genomes. Here we report a new method that uses SNP genotype data from parent-offspring trios to identify polymorphic deletions. We applied this method to data from the International HapMap Project to produce the first high-resolution population surveys of deletion polymorphism. Approximately 100 of these deletions have been experimentally validated using comparative genome hybridization on tiling-resolution oligonucleotide microarrays. Our analysis identifies a total of 586 distinct regions that harbor deletion polymorphisms in one or more of the families. Notably, we estimate that typical individuals are hemizygous for roughly 30-50 deletions larger than 5 kb, totaling around 550-750 kb of euchromatic sequence across their genomes. The detected deletions span a total of 267 known and predicted genes. Overall, however, the deleted regions are relatively gene-poor, consistent with the action of purifying selection against deletions. Deletion polymorphisms may well have an important role in the genetics of complex traits; however, they are not directly observed in most current gene mapping studies. Our new method will permit the identification of deletion polymorphisms in high-density SNP surveys of trio or other family data.

Databases, Genetic↗

PubMed2002

Beyond Mendel: an evolving view of human genetic disease transmission.

Methodological and conceptual advances in human genetics have led to the identification of an impressive number of human disease genes. This wealth of information has also revealed that the traditional distinction between Mendelian and complex disorders might sometimes be blurred. Genetic and mutational data on an increasing number of disorders have illustrated how phenotypic effects can result from the combined action of alleles in many genes. In this review, we discuss how an improved understanding of the genetic basis of multilocus inheritance is catalysing the transition from a segmented view of human genetic disease to a conceptual continuum between Mendelian and complex traits.

Alleles↗

PubMed2004

beta(3) Adrenergic receptor polymorphism and obesity-related phenotypes in hypertensive patients.

OBJECTIVES: Obesity is a complex trait that is affected by both environmental and genetic risk factors. The beta(3) adrenergic receptor (ADRB3) is expressed in adipose tissue and plays a role in energy metabolism. A missense mutation on codon 64 of this gene (W64R) is associated with receptor malfunction. Previous studies examining the relation between this polymorphism and obesity produced inconsistent findings. The current study assessed the association between the W64R genotype and obesity-related phenotypes, including body weight, BMI, and serum triglycerides, cholesterol, and glucose. RESEARCH METHODS AND PROCEDURES: We determined the ADRB3 W64R genotypes and fasting serum lipid and glucose concentrations for 695 hypertensive adults (336 men,359 women) from a rural county in Anhui Province, China. Multivariate linear regression models were fit to detect associations between the genetic polymorphism and obesity-related phenotypes. RESULTS: The ADRB3 W64R polymorphism was significantly associated with body weight and BMI in men but not in women. After controlling for potential confounding variables, men who were homozygous for the R64 allele were 11.8 kg heavier (p < 0.001) and had a BMI that was 3.7 kg/m(2) greater (p = 0.001) than men who were homozygous for the W64 allele. Serum concentrations of lipids and glucose were found not associated with the genetic polymorphism. DISCUSSION: The ADRB3 R64 allele was associated with increased body weight and BMI in men but not in women. The genetic association was not modified by triglyceride, cholesterol, blood glucose, or blood pressure levels of the subjects.

Adult↗

PubMed2022

Polygenic heterogeneity in antidepressant treatment and placebo response.

The genetic architecture of antidepressant response is poorly understood. Polygenic risk scores (PRS), exploration of placebo response and the use of sub-scales might provide insights. Here, we investigate the association between PRSs for relevant complex traits and response to vortioxetine treatment and placebo using clinical scales, including sub-scales and self-reported assessments. We collected a clinical test sample of Major Depressive Disorder (MDD) patients treated with vortioxetine (N = 907) or placebo (N = 455) from seven randomized, double-blind, clinical trials. In parallel, we obtained data from an observational web-based study of vortioxetine-treated patients (N = 642) with self-reported response. PRSs for antidepressant response, psychiatric disorders, and symptom traits were derived using summary statistics from well-powered genome-wide association studies (GWAS). Association tests were performed between the PRSs and treatment response in each of the two test samples and empirical p-values were evaluated. In the clinical test sample, no PRSs were significantly associated with response to vortioxetine treatment or placebo following Bonferroni correction. However, clinically assessed treatment response PRS was nominally associated with vortioxetine treatment and placebo response given by several secondary outcome scales (improvement on HAM-A, HAM-A Psychic Anxiety sub-scale, CPFQ & PDQ), (P ≤ 0.026). Further, higher subjective well-being PRS (P ≤ 0.033) and lower depression PRS (P = 0.01) were nominally associated with higher placebo response. In the self-reported test sample, higher schizophrenia PRS was significantly associated with poorer self-reported response (P = 0.0001). The identified PRSs explain a low proportion of the variance (1.2-5.3%) in placebo and treatment response. Although the results were limited, we believe that PRS associations bear unredeemed potential as a predictor for treatment response, as more well-powered and phenotypically similar GWAS bases become available.

Humans↗

PubMed2024

Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height.

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.

Humans↗

PubMed2026

Predicting genome-wide functional constraints with GPN-Star.

Genomic language models have emerged as a powerful approach for learning genome-wide functional constraints directly from DNA sequences1. However, standard genomic language models adapted from natural language processing often require large model sizes and computational resources, yet still fall short of classical evolutionary models in predictive tasks2-4. Here we introduce a genomic pretrained network with species tree and alignment representations (GPN-Star), which is a biologically grounded genomic language model featuring a phylogeny-aware architecture that leverages whole-genome alignments and species trees to model evolutionary relationships explicitly. Trained on alignments spanning vertebrate, mammal and primate evolutionary timescales, GPN-Star achieves state-of-the-art performance across a wide range of variant effect prediction tasks in both coding and non-coding regions of the human genome. Analyses across timescales show task-dependent advantages of modelling more recent versus deeper evolution. To demonstrate its potential to advance human genetics, we show that GPN-Star substantially outperforms previous methods in prioritizing pathogenic and fine-mapped genome-wide association study variants, yields strong enrichments of complex trait heritability and improves power in rare variant association testing5. Extending beyond humans, we train GPN-Star for five model organisms-Mus musculus, Gallus gallus, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana-demonstrating the robustness and generalizability of the framework. Taken together, these results position GPN-Star as a scalable, powerful and flexible tool for genome interpretation, well suited to leverage the growing abundance of comparative genomics data.

Journal Article↗

PubMed2025

A chromosome-level genome assembly of Coffea arabica L. var. 'Kona Typica'.

Coffea arabica L. var. 'Kona Typica' is renowned for its premium cup quality, but its vulnerability to pests and diseases limits production. To accelerate cultivar improvement, we generated a chromosome-level genome assembly of 'Kona Typica' using PacBio HiFi sequencing and Hi-C scaffolding technology. The final assembly spans 1.13 Gb, with a scaffold N50 of 50.50 Mb, organized into 22 chromosomes. BUSCO assessment indicated a high completeness at 99.1%. We annotated 65,458 protein-coding genes and identified 1,073,545 interspersed repeats, accounting for 65.16% of the genome. Analysis of transposon insertion ages revealed that most long terminal repeat retrotransposons proliferated after the polyploidization event. This high-quality genome assembly of 'Kona Typica' provides a valuable resource for exploring coffee genomic evolution and genetic mechanisms of complex traits, facilitating genomics studies and the development of improved coffee cultivars with enhanced disease resistance and quality traits.

Coffea↗