[Show abstract][Hide abstract]ABSTRACT: We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
[Show abstract][Hide abstract]ABSTRACT: Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.
[Show abstract][Hide abstract]ABSTRACT: It has been hypothesised that low frequency (1-5% MAF) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27,312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000 fold more significant than the previous sentinel variant and not in close LD (6 had MAF < 5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1-5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5-2.5 fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.
[Show abstract][Hide abstract]ABSTRACT: Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-related traits Consortium. Discovery was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, body mass index (BMI) and in a model ("Model 3") analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI. In Model 3, three variants reached genome-wide significance: rs13422522 (NYAP2, P=8.87 ×10(-11)), rs12454712 (BCL2, P=2.7×10(-8)) and rs10506418 (FAM19A2, P=1.9×10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardio-metabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
[Show abstract][Hide abstract]ABSTRACT: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
[Show abstract][Hide abstract]ABSTRACT: Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels. Here we show that both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels. Intriguingly, PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers, partly through a protein-protein interaction. PSAP-induced changes in PGRN levels and oligomerization replicate in human-derived fibroblasts obtained from a GRN mutation carrier, further supporting PSAP as a potential PGRN-related therapeutic target. Future studies should focus on addressing the relevance and cellular mechanism by which PGRN oligomeric species provide neuroprotection.
Full-text Article · Jun 2016 · Nature Communications
[Show abstract][Hide abstract]ABSTRACT: Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
[Show abstract][Hide abstract]ABSTRACT: Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer, some of which have been accompanied by impressive clinical advances. While these have occurred at a time when the incidence of kidney cancer among adults continues to increase in North America and most parts of Europe, elsewhere globally, rates remain stable. In order to summarize important achievements and identify prominent research questions that remain for kidney cancer, a workshop was organized by the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) in the Spring of 2015. Based on a review of major themes in population, genomic and clinical research, a series of ‘difficult questions’ were formulated, which should be given future priority within each of these areas.
[Show abstract][Hide abstract]ABSTRACT: Recent genetic studies have identified some alleles associated with higher BMI but lower risk of type 2 diabetes, hypertension and heart disease. These “favorable adiposity” alleles are collectively associated with lower insulin levels and higher subcutaneous-to-visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, test for interactions between BMI and favorable adiposity genetics and test effects separately in men and women.
In the UK Biobank the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 Kg/m2 [0.066,0.174]; p=1E-5) and higher body fat percentage (0.301 % [0.230,0.372]; p=1E-16) compared to the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favourable adiposity alleles were at: 0.837 OR [0.784,0.894] lower risk of type 2 diabetes (p=1E-7), -0.859 mmHg [-1.099,-0.618] lower systolic (p=3E-12) and -0.394 mmHg [-0.534,-0.254] lower diastolic blood pressure (p=4E-8), 0.935 OR [0.911,0.958] lower risk of hypertension (p=1E-7) and 0.921 OR [0.872,0.973] lower risk of heart disease (p=3E-3). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favourable body fat distribution, with a lower waist-hip ratio (-0.004 [-0.005,-0.003] 50% vs 50%; p=3E-14) but in men, the favourable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267,0.641] 50% vs 50%; p=2E-6) and higher waist-hip ratio (0.0013 [0.0003,0.0024] 50% vs 50%; p=0.01). Results were strengthened when meta-analysing with five additional studies. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score.
In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. While higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.
[Show abstract][Hide abstract]ABSTRACT: Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.