OBJECTIVES: To investigate the association of different measures of central (abdominal) and overall adiposity with autonomic nervous system (ANS) function, indexed by heart rate variability (HRV), in apparently healthy human adults. DESIGN AND MEASUREMENTS: Cross-sectional data of 8,538 participants (20% female, age: 41 ± 11 years, body mass index (BMI): 24 ± 4 kg/m2, waist circumference (WC): 91 ± 12 cm, waist-to-height ratio (WHtR): 0.45 ± 0.08) were available for analysis. RESULTS: All measures of adiposity were inversely correlated with vagally-mediated HRV indexed by RMSSD (all p<0.001). Strongest associations were found with WC and RMSSD (r = -0.29). Associations were stronger in males (WC r = -0.32) than in females (WC r = -0.23). Partial correlations revealed the same pattern for RMSSD (WC all pcc = -0.12 p<0.001; WC male pcc = -0.14 p<0.001; WC female pcc = -0.06 p<0.05). Correlation strength of BMI and WHtR with RMSSD were similar and significantly weaker compared to WC (p < .001) in unadjusted analysis. Overall, nonparametric Kendalls τb led to the same conclusions. CONCLUSION: The present data supports previous findings, that HRV is related to measures of adiposity in healthy individuals. In line with previous research, we found that WC is more strongly related to measures of HRV, indicating that WC best captures adiposity related risk.

OBJECTIVE: This study examined health and behavioral risk factors for infections that required hospitalization in postmenopausal women who were enrollees of a large health maintenance organization (HMO). METHODS: Participants were 1365 generally healthy women aged 55 to 80 years who were followed for up to 6 years. Infection diagnoses listed first in the automated hospital discharge records were used to identify hospitalizations for which infections were the primary cause of admission. Potential risk factors for these serious infections were identified from baseline questionnaire information and automated HMO records from before baseline and during follow‐up. Risks for infections associated with hospital admission were examined using multivariate logistic regression methods. RESULTS: Seventy‐three women had a total of 90 hospital admissions in which infection was the primary discharge diagnosis. Behaviors that were independent predictors of infection were physical inactivity (adj. odds ratio = 4.08; 95% CI, 1.73–9.63) and smoking (adj. odds ratio = 2.64; 95% CI, 1.11–6.26). Incident cancer and lung disease were also associated with increased risk of infection. These associations were independent of age, body mass index, functional status, and other measures of health. CONCLUSIONS: Modifiable risk factors such as physical inactivity and smoking may place older women at risk for serious infections although the causal link is yet to be explained. Further research in this area may lead to new strategies aimed at reducing the serious burden of infections in the older population.

Background

Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

Objective

To identify novel genetic variants associated with resting heart rate in African Americans.

Methods

Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)).

Results

Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

Conclusions

An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Objective

The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.

Methods

We used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.

Results

We found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.

Conclusions

Our findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.