Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke.

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMTmean-AS: HR = 1.39, 95%CI = 1.09-1.78; cIMTmin-AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMTmax-AS: [Formula: see text]=0.23, P=9.44 × 10-5; cIMTmean-AS: [Formula: see text]=0.21, P=3.00 × 10-4; cIMTmin-AS: [Formula: see text]=0.16, P=6.30 × 10-3). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMTmax-AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMTmean-AS: OR=1.09, 95%CI=0.93-1.26; cIMTmin-AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMTmax: beta=0.07, 95%CI = 0.01-0.13; AS-cIMTmean: beta=0.08, 95%CI = 0.01-0.15; AS-cIMTmin: beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.

Impact of gallstone disease on the risk of stroke and coronary artery disease: evidence from prospective observational studies and genetic analyses.

BACKGROUND: Despite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events - stroke and coronary artery disease (CAD). METHODS: We first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB). RESULTS: An overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19-1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke ([Formula: see text]=0.16, P = 6.00 × 10-4) and CAD ([Formula: see text]=0.27, P = 2.27 × 10-15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97-1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98-1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83-1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91-1.06), further supporting MR findings. CONCLUSIONS: Our work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.

A sex- and site-specific relationship between body mass index and osteoarthritis: evidence from observational and genetic analyses.

OBJECTIVE: We primarily aimed to investigate whether there are phenotypic and genetic links underlying body mass index (BMI) and overall osteoarthritis (OA). We then intended to explore whether the relationships differ across sexes and sites. METHOD: We first evaluated the phenotypic association between BMI and overall OA using data from the UK Biobank. We then investigated the genetic relationship leveraging summary statistics of the hitherto largest genome-wide association studies performed for BMI and overall OA. Finally, we repeated all analyses in a sex- (female, male) and site- (knee, hip, spine) specific manner. RESULTS: Observational analysis suggested an increased hazard of diagnosed OA per 5 kg/m2 increment in BMI (hazard ratio = 1.38, 95% confidence interval (CI) = 1.37-1.39). A positive overall genetic correlation was observed for BMI and OA (rg = 0.43, P = 4.72 × 10-133), corroborated by 11 significant local signals. Cross-trait meta-analysis identified 34 pleiotropic loci shared between BMI and OA, of which seven were novel. Transcriptome-wide association study revealed 29 shared gene-tissue pairs, targeting nervous, digestive, and exo/endocrine systems. Mendelian randomization demonstrated a robust BMI-OA causal relationship (odds ratio = 1.47, 95% CI = 1.42-1.52). A similar pattern of effects was observed in sex- and site-specific analyses, with BMI affecting OA comparably in both sexes and most strongly in the knee. CONCLUSION: Our work demonstrates an intrinsic relationship underlying BMI and overall OA, reflected by a pronounced phenotypic association, significant biological pleiotropy, and a putative causal link. Stratified analysis further reveals that the effects are distinct across sites and comparable across sexes.

Two are better than one: combining landscape genomics and common gardens for detecting local adaptation in forest trees.

Predicting likely species responses to an alteration of their local environment is key to decision-making in resource management, ecosystem restoration and biodiversity conservation practice in the face of global human-induced habitat disturbance. This is especially true for forest trees which are a dominant life form on Earth and play a central role in supporting diverse communities and structuring a wide range of ecosystems. In Europe, it is expected that most forest tree species will not be able to migrate North fast enough to follow the estimated temperature isocline shift given current predictions for rapid climate warming. In this context, a topical question for forest genetics research is to quantify the ability for tree species to adapt locally to strongly altered environmental conditions (Kremer et al. ). Identifying environmental factors driving local adaptation is, however, a major challenge for evolutionary biology and ecology in general but is particularly difficult in trees given their large individual and population size and long generation time. Empirical evaluation of local adaptation in trees has traditionally relied on fastidious long-term common garden experiments (provenance trials) now supplemented by reference genome sequence analysis for a handful of economically valuable species. However, such resources have been lacking for most tree species despite their ecological importance in supporting whole ecosystems. In this issue of Molecular Ecology, De Kort et al. () provide original and convincing empirical evidence of local adaptation to temperature in black alder, Alnus glutinosa L. Gaertn, a surprisingly understudied keystone species supporting riparian ecosystems. Here, De Kort et al. () use an innovative empirical approach complementing state-of-the-art landscape genomics analysis of A. glutinosa populations sampled in natura across a regional climate gradient with phenotypic trait assessment in a common garden experiment (Fig. ). By combining the two methods, De Kort et al. () were able to detect unequivocal association between temperature and phenotypic traits such as leaf size as well as with genetic loci putatively under divergent selection for temperature. The research by De Kort et al. () provides valuable insight into adaptive response to temperature variation for an ecologically important species and demonstrates the usefulness of an integrated approach for empirical evaluation of local adaptation in nonmodel species (Sork et al. ).

Observational and genetic analyses of the bidirectional relationship between depression and hypertension.

BACKGROUND: While the association between depression and hypertension has been extensively investigated, the pattern and nature of such association remain inconclusive. We sought to investigate the bidirectional relationship between depression and hypertension and its causal. METHODS: We first performed observational analyses using longitudinal data from the UK Biobank. We then performed genetic analyses leveraging summary statistics from large-scale genome-wide association studies (GWASs) conducted in European ancestry for depression and hypertension. RESULTS: Observational analysis suggested a significant bidirectional phenotypic association between depression and hypertension (Depression â†’ Hypertension: HR = 1.27, 95 % CI: 1.19, 1.36; Hypertension â†’ Depression: HR = 1.65, 95 % CI: 1.58, 1.72). Linkage disequilibrium score regression demonstrated a positive genetic correlation between the two conditions (rg=0.15, P = 5.75 × 10-10). Bidirectional two-sample Mendelian randomization (MR) suggested that genetic liability to depression was significantly associated with an increased risk of hypertension (OR = 1.27, 95 % CI: 1.12, 1.43), while the genetic liability to hypertension was not associated with the risk of depression (OR = 1.01, 95 % CI: 0.99, 1.03). Multivariate MR, after adjusting for smoking, drinking, and body mass index, further supported an independent causal effect of genetic liability to depression on hypertension risk (OR = 1.10, 95 % CI: 1.02, 1.18). LIMITATIONS: (1) interference of confounders, (2) absence of adequate statistical power, and (3) limitation to European populations. CONCLUSION: Our study indicates depression is a causal risk factor for hypertension, whereas the reverse maybe not. Findings support that prevention of depression might help in decreasing hypertension incidence.

Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activity.

BACKGROUND: The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, respectively, have not been provided. METHODS: MG, GO and 3-DG were measured by LC-MS in 1304 serum samples of two populations (KORA, n = 482; BiDirect, n = 822) and assessed for associations with genome-wide SNPs (GWAS) and with phenome-wide traits. Redundancy analysis (RDA) was used to identify major independent trait associations. FINDINGS: Mutual correlations of dicarbonyls were highly significant, being stronger between MG and GO (ρ = 0.6) than between 3-DG and MG or GO (ρ = 0.4). Significant phenotypic results included associations of all dicarbonyls with sex, waist-to-hip ratio, glomerular filtration rate (GFR), gamma-glutamyltransferase (GGT), and hypertension, of MG and GO with age and C-reactive protein, of GO and 3-DG with glucose and antidiabetics, of MG with contraceptives, of GO with ferritin, and of 3-DG with smoking. RDA revealed GFR, GGT and, in case of 3-DG, glucose as major contributors to dicarbonyl variance. GWAS did not identify genome-wide significant loci. SNPs previously associated with glyoxalase activity did not reach nominal significance. When multiple testing was restricted to the lead SNPs of GWASs on the traits selected by RDA, 3-DG was found to be associated (p = 2.3 × 10-5) with rs1741177, an eQTL of NF-κB inhibitor NFKBIA. INTERPRETATION: This large-scale, population-based study has identified numerous associations, with GFR and GGT being of pivotal importance, providing unbiased perspectives on dicarbonyls beyond the current state. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Munich, German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF).

Identifying genetic variation associated with environmental gradients and drought-tolerance phenotypes in ponderosa pine.

As climate changes, understanding the genetic basis of local adaptation in plants becomes an ever more pressing issue. Combining genotype-environment association (GEA) with genotype-phenotype association (GPA) analysis has an exciting potential to uncover the genetic basis of environmental responses. We use these approaches to identify genetic variants linked to local adaptation to drought in Pinus ponderosa. Over 4 million Single Nucleotide Polymorphisms (SNPs) were identified using 223 individuals from across the Sierra Nevada of California. 927,740 (22.3%) SNPs were retained after filtering for proximity to genes and used in our association analyses. We found 1374 associated with five major climate variables, with the largest number (1151) associated with April 1st snowpack. We also conducted a greenhouse study with various drought-tolerance traits measured in first-year seedlings of a subset of the genotyped trees grown in the greenhouse. 796 SNPs were associated with control-condition trait values, while 1149 were associated with responsiveness of these traits to drought. While no individual SNPs were associated with both the environmental variables and the measured traits, several annotated genes were associated with both, particularly those involved in cell wall formation, biotic and abiotic stress responses, and ubiquitination. However, the functions of many of the associated genes have not yet been determined due to the lack of gene annotation information for conifers. Future studies are needed to assess the developmental roles and ecological significance of these unknown genes.

The HLA complex and coeliac disease.

The Human Leukocyte Antigen (HLA) has a crucial role in the development and pathogenesis of coeliac disease (CD). The genes HLA-DQA1 and HLA-DQB1, both lying in this region and encoding the HLA-DQ heterodimer, are the main genetic predisposing factors to CD. Approximately 90% of CD patients carry the heterodimer HLA-DQ2.5, leaving only a small proportion of patients with lower risk heterodimers (HLA-DQ8, HLA-DQ2.2 or HLA-DQ7.5). These HLA-DQ molecules act as receptors present in the surface of antigen presenting cells and show high affinity for deamidated gluten peptides, which bind and present to CD4+ T cells. This triggers the immunological reaction that evolves into CD. Since specific HLA genetics is present in almost the totality of CD patients, HLA typing has a very high negative predictive value, and it can be used to support diagnosis in specific scenarios. HLA risk has been associated to different CD-related features, such as age at onset, clinical outcomes, antibody levels and grade of histological lesion; but further research is needed. HLA-DQ genotypes have been also suggested to modulate the composition of the gut microbiota.

Lineage diversification of pigeon paramyxovirus effect re-emergence potential in chickens.

Genotype VI-paramyxovirus (GVI-PMV1) is a major cause of epidemic Newcastle-like disease in Columbiformes. This genotype of avian paramyxovirus type 1 has diversified rapidly since its introduction into the US in 1982 resulting in two extant lineages, which have different population growth properties. Although some GVI-PMV1s replicate poorly in chickens, it is possible that variants with different replicative or pathogenic potential in chickens exist among the genetically-diverse GVI-PMV1s strains. To determine if variants of Columbiform GVI-PMV1 with different phylogenetic affiliations have distinct phenotypic properties in chickens, we investigated the replicative properties of 10 naturally circulating pigeon-derived isolates representing four subgroups of GVI-PMV1 in primary chicken lung epithelial cells and in chicken embryos. Our data demonstrate that GVI-PMV1 variants have different infection phenotypes in their chicken source host and that properties reflect subgroup affiliation. These subgroup replicative properties are consistent with observed dynamics of viral population growth.