The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.
We ...conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.
In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio OR = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).
We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.
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.
Background
The pool of studies examining ethnoracial differences in hospice use and end‐of‐life hospitalizations among patients with dementia is limited and results are conflicting. This study ...examined how dementia end‐of‐life care utilization and patient treatment preferences differ by race and ethnicity.
Methods
Using U.S. national survey data from the Health and Retirement Study linked with Medicare and Medicaid claims, our sample included 5,058 beneficiaries aged ≥65 years diagnosed with dementia who died in 2000‐2016. We examined the frequency and costs of hospice care, emergency department (ED) visits, and hospitalizations during the last 180 days of life among Medicare decedents with dementia. We analyzed the proportion of dementia decedents with advance care planning and their end‐of‐life care preferences.
Results
Less than half of beneficiaries with dementia in our sample (48%) used hospice in the last 180 days of life; of these, one in three hospice users received the service for seven days or less. In adjusted analysis, non‐Hispanic (NH) Blacks, nursing home residents, and survey respondents represented by a proxy were less likely to use hospice, whereas older age, females, higher education, more severe cognitive impairment, and more IADL limitations were associated with higher hospice enrollment. Among dementia decedents, NH Blacks and Hispanics used more ED and inpatient services and incurred >50% higher inpatient expenditures at the end of life, compared with NH whites. More NH Black and Hispanic beneficiaries with dementia enrolled in hospice were subsequently admitted to the ED or hospital before death. The proportion of dementia beneficiaries completing advance care planning was significantly lower among NH Blacks and Hispanics compared with NH whites (21% and 21% vs. 57%, p<0.01). More NH Black and Hispanic decedents with dementia had written instructions choosing all care possible to prolong life, whereas more NH whites preferred to limit care in certain situations, withhold treatments, and forgo extensive life‐prolonging measures.
Conclusion
Our results highlighted substantial unmet end‐of‐life care needs among older adults with dementia, especially among NH Blacks and Hispanics. Medicare should consider alternative payment models to promote culturally competent end‐of‐life care and reduce low‐value interventions and costs among the population with dementia.
Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance ...use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.
We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.
Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.
Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have ...been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
Background
Previous work using data from the UK Biobank has shown that both unfavorable lifestyle and genetic risk are associated with higher dementia risk; however, it is not known whether these ...results transfer to more representative samples and across country.
Methods
Data come from the Health and Retirement Study (HRS), a cohort study of Americans 65 years of age and older without dementia at baseline. Adults of European descent are included in the analyses. Dementia was determined using Medicare claims from 2000‐2016. 6,870 individuals were followed for an average of 11 years (Median 12; IQR 8.6 – 15.6 years) with mean age of 68.8 (5.4). Polygenic scores (PGS) for dementia from 2 large, replicated genome‐wide association studies (Lambert et al. and Kunkle et al.) were used along with a weighted lifestyle score (including measures of smoking, drinking, and physical activity) to predict incident dementia. The association between the PGS and lifestyle was assessed using ordered logistic regression. Cox proportional hazard regression models were used to examine the association of genetic risk, lifestyle, and the interaction with time to incident dementia.
Result
Overall, 22.9% (n=1,580) were diagnosed with dementia during the observation period. 23.8% of participants had a favorable lifestyle, 50.7% had a moderately favorable lifestyle, and 25.5% had an unfavorable lifestyle. There was no significant association between the lifestyle score and either PGS. The effect of PGS on time to dementia was significant with and without adjustment for covariates (age, sex, education, wealth, comorbidities) with higher genetic risk conferring an increased risk for dementia (hazard ratio highest PGS group compared to lowest 1.37 95% CI 1.17, 1.61). Individuals with a favorable lifestyle at baseline were significantly less likely to develop dementia adjusting for PGS and covariates (adjusted hazard ratio 0.85 95% CI, 0.74‐0.99). Results were similar regardless of which PGS was used. There was no significant interaction between genetic risk and lifestyle.
Conclusion
These findings demonstrate that an unhealthy lifestyle and genetic risk are associated with higher dementia risk. Results from a nationally‐representative sample of older adults in the United States are comparable with those from UK Biobank.
Abstract
Background
Previous work using data from the UK Biobank has shown that both unfavorable lifestyle and genetic risk are associated with higher dementia risk; however, it is not known whether ...these results transfer to more representative samples and across country.
Methods
Data come from the Health and Retirement Study (HRS), a cohort study of Americans 65 years of age and older without dementia at baseline. Adults of European descent are included in the analyses. Dementia was determined using Medicare claims from 2000‐2016. 6,870 individuals were followed for an average of 11 years (Median 12; IQR 8.6 – 15.6 years) with mean age of 68.8 (5.4). Polygenic scores (PGS) for dementia from 2 large, replicated genome‐wide association studies (Lambert et al. and Kunkle et al.) were used along with a weighted lifestyle score (including measures of smoking, drinking, and physical activity) to predict incident dementia. The association between the PGS and lifestyle was assessed using ordered logistic regression. Cox proportional hazard regression models were used to examine the association of genetic risk, lifestyle, and the interaction with time to incident dementia.
Result
Overall, 22.9% (n=1,580) were diagnosed with dementia during the observation period. 23.8% of participants had a favorable lifestyle, 50.7% had a moderately favorable lifestyle, and 25.5% had an unfavorable lifestyle. There was no significant association between the lifestyle score and either PGS. The effect of PGS on time to dementia was significant with and without adjustment for covariates (age, sex, education, wealth, comorbidities) with higher genetic risk conferring an increased risk for dementia (hazard ratio highest PGS group compared to lowest 1.37 95% CI 1.17, 1.61). Individuals with a favorable lifestyle at baseline were significantly less likely to develop dementia adjusting for PGS and covariates (adjusted hazard ratio 0.85 95% CI, 0.74‐0.99). Results were similar regardless of which PGS was used. There was no significant interaction between genetic risk and lifestyle.
Conclusion
These findings demonstrate that an unhealthy lifestyle and genetic risk are associated with higher dementia risk. Results from a nationally‐representative sample of older adults in the United States are comparable with those from UK Biobank.
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