Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults.

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up. METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods. RESULTS: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]). CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

Associations of autozygosity with a broad range of human phenotypes.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

Ethnic differences in sudden cardiac arrest resuscitation.

OBJECTIVE: Ethnic differences in sudden cardiac arrest resuscitation have not been fully explored and studies have yielded inconsistent results. We examined the association of ethnicity with factors affecting sudden cardiac arrest outcomes. METHODS: Retrospective cohort study of 3551 white, 440 black and 297 Asian sudden cardiac arrest cases in Seattle and King County, Washington, USA. RESULTS: Compared with whites, blacks and Asians were younger, had lower socioeconomic status and were more likely to have diabetes, hypertension and end-stage renal disease (all p<0.001). Blacks and Asians were less likely to have a witnessed arrest (whites 57.6%, blacks 52.1%, Asians 46.1%, p<0.001) or receive bystander cardiopulmonary resuscitation (whites 50.9%, blacks 41.4%, Asians 47.1%, p=0.001), but had shorter average emergency medical services response time (mean in minutes: whites 5.18, blacks 4.75, Asians 4.85, p<0.001). Compared with whites, blacks were more likely to be found in pulseless electrical activity (blacks 20.9% vs whites 16.6%, p<0.001), and Asians were more likely to be found in asystole (Asians 41.1% vs whites 30.0%, p<0.001). One of the strongest predictors of resuscitation outcomes was initial cardiac rhythm with 25% of ventricular fibrillation, 4% of patients with pulseless electrical activity and 1% of patients with asystole surviving to hospital discharge (adjusted OR of resuscitation in pulseless electrical activity compared with ventricular fibrillation: 0.30, 95% CI 0.24 to 0.34, p<0.001, adjusted OR of resuscitation in asystole relative to ventricular fibrillation 0.21, 95% CI 0.17 to 0.26, p<0.001). Survival to hospital discharge was similar across all three ethnicities. CONCLUSIONS: While there were differences in some prognostic characteristics between blacks, whites and Asians, we did not detect a significant difference in survival following sudden cardiac arrest between the three ethnic groups. There was, however, an ethnic difference in presenting rhythm, with pulseless electrical activity more prevalent in blacks and asystole more prevalent in Asians.