Understanding complex traits: from farmers to pharmas

A report on the 4th International Conference on Quantitative Genetics (ICQG4), Edinburgh, UK, June 17-22, 2012

Participation bias in the UK Biobank distorts genetic associations and downstream analyses

While volunteer-based studies such as the UK Biobank have become the cornerstone of genetic epidemiology, the participating individuals are rarely representative of their target population. To evaluate the impact of selective participation, here we derived UK Biobank participation probabilities on the basis of 14 variables harmonized across the UK Biobank and a representative sample. We then conducted weighted genome-wide association analyses on 19 traits. Comparing the output from weighted genome-wide association analyses (neffective = 94,643 to 102,215) with that from standard genome-wide association analyses (n = 263,464 to 283,749), we found that increasing representativeness led to changes in SNP effect sizes and identified novel SNP associations for 12 traits. While heritability estimates were less impacted by weighting (maximum change in h2, 5%), we found substantial discrepancies for genetic correlations (maximum change in rg, 0.31) and Mendelian randomization estimates (maximum change in βSTD, 0.15) for socio-behavioural traits. We urge the field to increase representativeness in biobank samples, especially when studying genetic correlates of behaviour, lifestyles and social outcomes

Genome-wide association, prediction and heritability in bacteria with application to Streptococcus pneumoniae

Whole-genome sequencing has facilitated genome-wide analyses of association, prediction and heritability in many organisms. However, such analyses in bacteria are still in their infancy, being limited by difficulties including genome plasticity and strong population structure. Here we propose a suite of methods including linear mixed models, elastic net and LD-score regression, adapted to bacterial traits using innovations such as frequency-based allele coding, both insertion/deletion and nucleotide testing and heritability partitioning. We compare and validate our methods against the current state-of-art using simulations, and analyse three phenotypes of the major human pathogen Streptococcus pneumoniae, including the first analyses of minimum inhibitory concentrations (MIC) for penicillin and ceftriaxone. We show that the MIC traits are highly heritable with high prediction accuracy, explained by many genetic associations under good population structure control. In ceftriaxone MIC, this is surprising because none of the isolates are resistant as per the inhibition zone criteria. We estimate that half of the heritability of penicillin MIC is explained by a known drug-resistance region, which also contributes a quarter of the ceftriaxone MIC heritability. For the within-host carriage duration phenotype, no associations were observed, but the moderate heritability and prediction accuracy indicate a moderately polygenic trait.Peer reviewe

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast

Large structural variations (SVs) within genomes are more challenging to identify than smaller genetic variants but may substantially contribute to phenotypic diversity and evolution. We analyse the effects of SVs on gene expression, quantitative traits and intrinsic reproductive isolation in the yeast Schizosaccharomyces pombe. We establish a high-quality curated catalogue of SVs in the genomes of a worldwide library of S. pombe strains, including duplications, deletions, inversions and translocations. We show that copy number variants (CNVs) show a variety of genetic signals consistent with rapid turnover. These transient CNVs produce stoichiometric effects on gene expression both within and outside the duplicated regions. CNVs make substantial contributions to quantitative traits, most notably intracellular amino acid concentrations, growth under stress and sugar utilization in winemaking, whereas rearrangements are strongly associated with reproductive isolation. Collectively, these findings have broad implications for evolution and for our understanding of quantitative traits including complex human diseases

Graph pangenome captures missing heritability and empowers tomato breeding

Missing heritability in genome-wide association studies defines a major problem in genetic analyses of complex biological traits(1,2). The solution to this problem is to identify all causal genetic variants and to measure their individual contributions(3,4). Here we report a graph pangenome of tomato constructed by precisely cataloguing more than 19 million variants from 838 genomes, including 32 new reference-level genome assemblies. This graph pangenome was used forgenome-wide association study analyses and heritability estimation of 20,323 gene-expression and metabolite traits. The average estimated trait heritability is 0.41 compared with 0.33 when using the single linear reference genome. This 24% increase in estimated heritability is largely due to resolving incomplete linkage disequilibrium through the inclusion of additional causal structural variants identified using the graph pangenome. Moreover, by resolving allelic and locus heterogeneity, structural variants improve the power to identify genetic factors underlying agronomically important traits leading to, for example, the identification of two new genes potentially contributing to soluble solid content. The newly identified structural variants will facilitate genetic improvement of tomato through both marker-assisted selection and genomic selection. Our study advances the understanding of the heritability of complex traits and demonstrates the power of the graph pangenome in crop breeding

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

ObjectiveTo characterize, among European and Han Chinese populations, the genetic predictors ofmaculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepilepticdrugs.MethodsWe conducted a case-control genome-wide association study of autosomal genotypes, in-cluding Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent.Results from each cohort were meta-analyzed.ResultsWe report an association between a rare variant in the complement factor H–related 4(CFHR4) gene and phenytoin-induced MPE in Europeans (p= 4.5 × 10–11; odds ratio [95%confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium witha missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our resultsreinforce the association betweenHLA-A*31:01and carbamazepine hypersensitivity. We didnot identify significant genetic associations with MPE among Han Chinese patients.ConclusionsThe identification of genetic predictors of MPE in CFHR4 and CFH, members of thecomplement factor H–related protein family, suggest a new link between regulation of thecomplement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast

Large structural variations (SVs) within genomes are more challenging to identify than smaller genetic variants but may substantially contribute to phenotypic diversity and evolution. We analyse the effects of SVs on gene expression, quantitative traits and intrinsic reproductive isolation in the yeast Schizosaccharomyces pombe. We establish a high-quality curated catalogue of SVs in the genomes of a worldwide library of S. pombe strains, including duplications, deletions, inversions and translocations. We show that copy number variants (CNVs) show a variety of genetic signals consistent with rapid turnover. These transient CNVs produce stoichiometric effects on gene expression both within and outside the duplicated regions. CNVs make substantial contributions to quantitative traits, most notably intracellular amino acid concentrations, growth under stress and sugar utilization in winemaking, whereas rearrangements are strongly associated with reproductive isolation. Collectively, these findings have broad implications for evolution and for our understanding of quantitative traits including complex human diseases

Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics

Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment