Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such ...autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.
Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require ...exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes, of which five (near FOXO3, SLC4A7, LINC02513, ZW10, and FGD6) have not been reported previously at genome-wide significance. The majority of these 10 loci are associated with cardiovascular disease and some affect the expression of genes known to change their activity with age. In total, we implicate 78 genes, and find these to be enriched for ageing pathways previously highlighted in model organisms, such as the response to DNA damage, apoptosis, and homeostasis. Finally, we identify a pathway worthy of further study: haem metabolism.
To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a ...three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Male pattern baldness (MPB) or androgenetic alopecia is one of the most common conditions affecting men, reaching a prevalence of ~50% by the age of 50; however, the known genes explain little of the ...heritability. Here, we present the results of a genome-wide association study including more than 70,000 men, identifying 71 independently replicated loci, of which 30 are novel. These loci explain 38% of the risk, suggesting that MPB is less genetically complex than other complex traits. We show that many of these loci contain genes that are relevant to the pathology and highlight pathways and functions underlying baldness. Finally, despite only showing genome-wide genetic correlation with height, pathway-specific genetic correlations are significant for traits including lifespan and cancer. Our study not only greatly increases the number of MPB loci, illuminating the genetic architecture, but also provides a new approach to disentangling the shared biological pathways underlying complex diseases.
Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein ...quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to ...evaluate its clinical relevance.
A phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization.
In this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Women on average live longer than men, which seems to suggest that women also age slower than men. However, the potential difference in the pace of aging between the sexes is a relatively ...controversial topic, and both positions, i.e. "men age faster" and "men and women age at the same pace", have found some support. We therefore employ parametric models previously established in model organisms as well as two nonparametric approaches to compare the pace of aging between the sexes using freely available mortality data from 13 high-income countries. Our results support the hypothesis that men age faster than women while also suggesting that the difference is small and that from a practical standpoint male mortality rates behave similarly to the mortality rates of women approximately eight years their senior.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Lifespan is a trait of enormous personal interest. Research into the biological basis of human lifespan, however, is hampered by the long time to death. Using a novel approach of regressing (272,081) ...parental lifespans beyond age 40 years on participant genotype in a new large data set (UK Biobank), we here show that common variants near the apolipoprotein E and nicotinic acetylcholine receptor subunit alpha 5 genes are associated with lifespan. The effects are strongly sex and age dependent, with APOE ɛ4 differentially influencing maternal lifespan (P=4.2 × 10(-15), effect -1.24 years of maternal life per imputed risk allele in parent; sex difference, P=0.011), and a locus near CHRNA3/5 differentially affecting paternal lifespan (P=4.8 × 10(-11), effect -0.86 years per allele; sex difference P=0.075). Rare homozygous carriers of the risk alleles at both loci are predicted to have 3.3-3.7 years shorter lives.
The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we ...developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan.
RATIONALE:One measure of protein glycosylation (GlycA) has been reported to predict higher cardiovascular risk by reflecting inflammatory pathways.
OBJECTIVE:The main objective of this study is to ...assess the role of a comprehensive panel of IgG glycosylation traits on traditional risk factors for cardiovascular disease and on presence of subclinical atherosclerosis in addition to GlycA.
METHODS AND RESULTS:We measured 76 IgG glycosylation traits in 2970 women (age range, 40–79 years) from the TwinsUK cohort and correlated it to their estimated 10-year atherosclerotic cardiovascular disease risk score and their carotid and femoral plaque measured by ultrasound imaging. Eight IgG glycan traits are associated with the 10-year atherosclerotic cardiovascular disease risk score after adjusting for multiple tests and for individual risk factors—5 with increased risk and 3 with decreased risk. These glycans replicated in 967 women from ORCADES cohort (Orkney Complex Disease Study), and 6 of them were also associated in 845 men. A linear combination of IgG glycans and GlycA is also associated with presence of carotid (odds ratio, 1.55; 95% confidence interval, 1.25–1.93; P=7.5×10) and femoral (odds ratio, 1.32; 95% confidence interval, 1.06–1.64; P=0.01) plaque in a subset of women with atherosclerosis data after adjustment for traditional risk factors. One specific glycosylation trait, GP18-the percentage of FA2BG2S1 glycan in total IgG glycans, was negatively correlated with very-low-density lipoprotein and triglyceride levels in serum and with presence of carotid plaque (odds ratio, 0.60; 95% confidence interval, 0.50–0.71; P=5×10).
CONCLUSIONS:We find molecular pathways linking IgG to arterial lesion formation. Glycosylation traits are independently associated with subclinical atherosclerosis. One specific trait related to the sialylated N-glycan is negatively correlated with cardiovascular disease risk, very-low-density lipoprotein and triglyceride serum levels, and presence of carotid plaque.
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