Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance

Observation of the Bc+→J/ψπ+π0B_c^+ \to J/\psi \pi^+ \pi^0 decay

The first observation of the $B_c^+ \to J/\psi \pi^+ \pi^0$ decay is reported with high significance using proton-proton collision data, corresponding to an integrated luminosity of 9 fb$^{-1}$, collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV. The ratio of its branching fraction relative to the $B_c^+ \to J/\psi \pi^+$ channel is measured to be $$\frac{ {\cal{B}}_{( B_c^+ \to J/\psi \pi^+\pi^0 ) }} { {\cal{B}}_{( B_c^+ \to J/\psi \pi^+ ) }} = 2.80 \pm 0.15 \pm 0.11 \pm 0.16 \,,$$ where the first uncertainty is statistical, the second systematic and the third related to imprecise knowledge of the branching fractions for $B^+ \to J/\psi K^{*+}$ and $B^+ \to J/\psi K^+$ decays, which are used to determine the $\pi^0$ detection efficiency. The $\pi^+\pi^0$ mass spectrum is found to be consistent with the dominance of an intermediate $\rho^+$ contribution in accordance with a model based on QCD factorisation.The first observation of the ${B}_c^{+}\to J/\psi {\pi}^{+}{\pi}^0$ decay is reported with high significance using proton-proton collision data, corresponding to an integrated luminosity of 9 fb$^{−1}$, collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV. The ratio of its branching fraction relative to the ${B}_c^{+}\to J/\psi {\pi}^{+}$ channel is measured to be$\frac{{\mathcal{B}}_{B_c^{+}\to J/\psi {\pi}^{+}{\pi}^0}}{{\mathcal{B}}_{B_c^{+}\to J/\psi {\pi}^{+}}}=2.80\pm 0.15\pm 0.11\pm 0.16,$where the first uncertainty is statistical, the second systematic and the third related to imprecise knowledge of the branching fractions for B$^{+}$ → J/ψK$^{*+}$ and ${B}_c^{+}\to J/\psi {\pi}^{+}$ decays, which are used to determine the π$^{0}$ detection efficiency. The π$^{+}$π$^{0}$ mass spectrum is found to be consistent with the dominance of an intermediate ρ$^{+}$ contribution in accordance with a model based on QCD factorisation.[graphic not available: see fulltext]The first observation of the $B_c^+ \to J/\psi \pi^+ \pi^0$ decay is reported with high significance using proton-proton collision data, corresponding to an integrated luminosity of 9fb$^{-1}$, collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV. The ratio of its branching fraction relative to the $B_c^+ \to J/\psi \pi^+$ channel is measured to be $$\frac{ {\cal{B}}( B_c^+ \to J/\psi \pi^+\pi^0 ) } { {\cal{B}}( B_c^+ \to J/\psi \pi^+ ) } = 2.80 \pm 0.15 \pm 0.11 \pm 0.16 \,,$$ where the first uncertainty is statistical, the second systematic and the third related to imprecise knowledge of the branching fractions for $B^+ \to J/\psi K^{*+}$ and $B^+ \to J/\psi K^+$ decays, which are used to determine the $\pi^0$ detection efficiency. The $\pi^+\pi^0$ mass spectrum is found to be consistent with the dominance of an intermediate $\rho^+$ contribution in accordance with a model based on QCD factorisation

Study of Bc+→χcπ+B_c^+ \rightarrow \chi_c \pi^+ decays

International audienceA study of $B_c^+ \rightarrow \chi_c \pi^+$ decays is reported using proton-proton collision data, collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV, corresponding to an integrated luminosity of 9fb$^{-1}$. The decay $B_c^+ \rightarrow \chi_{c2} \pi^+$ is observed for the first time, with a significance exceeding seven standard deviations. The relative branching fraction with respect to the $B_c^+ \rightarrow J/\psi \pi^+$ decay is measured to be $$\frac{\mathcal{B}_{B_c^+ \rightarrow \chi_{c2} \pi^+}} {\mathcal{B}_{B_c^+ \rightarrow J/\psi \pi^+}} = 0.37 \pm 0.06 \pm 0.02 \pm 0.01 ,$$ where the first uncertainty is statistical, the second is systematic, and the third is due to the knowledge of the $\chi_c \rightarrow J/\psi \gamma$ branching fraction. No significant $B_c^+ \rightarrow \chi_{c1} \pi^+$ signal is observed and an upper limit for the relative branching fraction for the $B_c^+ \rightarrow \chi_{c1} \pi^+$ and $B_c^+ \rightarrow \chi_{c2} \pi^+$ decays of $$\frac{\mathcal{B}_{B_c^+ \rightarrow \chi_{c1} \pi^+}} {\mathcal{B}_{B_c^+ \rightarrow \chi_{c2} \pi^+}} < 0.49$$ is set at the 90% confidence level