Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium.

BACKGROUND: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. METHOD AND RESULTS: Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65-75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. CONCLUSIONS: For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia.

Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT-BPD and SCZ-BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes, IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions-the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7×10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.

Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.

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.

The association of genetic variants in interleukin-1 genes with cognition: findings from the cardiovascular health study.

The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive deterioration through pathology due to a dementing disorder or due to an aging process. Study of genetic variants in the IL1 genes has been mostly limited to diseases such as Alzheimer's, however, there may be benefit to studying a continuous measure of cognition. Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically significant minor allele SNP associations with baseline performance on the 3MS in the IL1RN gene for Caucasians (rs17042917: beta=0.47, 95%CI=0.09, 0.85, p=0.016; rs4251961: beta=-0.36, 95%CI=-0.13,-0.60, p=0.0027; rs931471: beta=0.39, 95%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African Americans (rs1143627: beta=1.6, 95%CI=0.48, 2.8; p=0.006 and rs1143634: beta=2.09, 95%CI=0.39, 3.8; p=0.016). Associations appear to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia, effect sizes and statistical significance attenuated. These results provide supporting evidence that genetic variants in IL1 genes may be involved in inflammatory-related lowered cognition, that higher education may modify genetic predisposition, and that these associations may be driven by a dementia process.

Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty.

OBJECTIVE: This project was designed to follow-up prior evidence that demonstrated a significant association between vitamin B12 transport and metabolism and the frailty syndrome in community-dwelling older women. The cross-sectional relationship between genetic variants within six candidate genes along this pathway with serum methylmalonic acid (MMA) levels and frailty was evaluated in this same population of older women. METHODS: Baseline measures were collected prior to folate fortification from 326 women in the Women's Health and Aging Studies I and II. Odds ratios and statistical tests were estimated for single SNP and haplotype via linear regression models for serum MMA, a marker for available vitamin B12, and in logistic regression models for frailty. RESULTS: Fifty-six SNPs from CBS, MTHFR, MTR, MTRR, TCN1 and TCN2 genes were genotyped. Several SNPs in MTHFR, MTR and MTRR demonstrated a modest association to elevated MMA, while SNPs in TCN2 showed significant association to the frailty syndrome. TCN2 polymorphisms, particularly one SNP reported to be in perfect LD with functional variant Pro259Arg, were significantly associated with increased odds of frailty, after adjustment for age, presence of cardiovascular disease and elevated MMA (OR = 2.25, p-value = 0.009). CONCLUSIONS: Using MMA as a marker for vitamin B12, these results suggest that TCN2 gene variants may lead to decreased vitamin B12 availability, leading to reduced energy metabolism, ultimately contributing to frailty pathology. Further studies to determine the biological role of functional TCN2 polymorphisms in frailty are needed.

NOS1AP variant associated with incidence of type 2 diabetes in calcium channel blocker users in the Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: To validate the reported association between rs10494366 in NOS1AP (the gene encoding nitric oxide synthase-1 adaptor protein) and the incidence of type 2 diabetes in calcium channel blocker (CCB) users and to identify additional NOS1AP variants associated with type 2 diabetes risk. METHODS: Data from 9 years of follow-up in 9,221 middle-aged white and 2,724 African-American adults free of diabetes at baseline from the Atherosclerosis Risk in Communities study were analysed. Nineteen NOS1AP variants were examined for associations with incident diabetes and fasting glucose levels stratified by baseline CCB use. RESULTS: Prevalence of CCB use at baseline was 2.7% (n = 247) in whites and 2.3% (n = 72) in African-Americans. Among white CCB users, the G allele of rs10494366 was associated with lower diabetes incidence (HR 0.57, 95% CI 0.35-0.92, p = 0.016). The association was marginally significant after adjusting for age, sex, obesity, smoking, alcohol use, physical activity, hypertension, heart rate and electrocardiographic QT interval (HR 0.63, 95% CI 0.38-1.04, p = 0.052). rs10494366 was associated with lower average fasting glucose during follow-up (p = 0.037). No other variants were associated with diabetes risk in CCB users after multiple-testing correction. No associations were observed between any NOS1AP variant and diabetes development in non-CCB users. NOS1AP variants were not associated with diabetes risk in either African-American CCB users or non-CCB users. CONCLUSIONS/INTERPRETATION: We have independently replicated the association between rs10494366 in NOS1AP and incident diabetes among white CCB users. Further exploration of NOS1AP variants and type 2 diabetes and functional studies of NOS1AP in type 2 diabetes pathology is warranted.

IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women.

Elevated levels of the inflammatory cytokine IL-6 are associated with the development of disability, frailty, and mortality in older adults. These outcomes are likely mediated through inflammatory activity that alters hormones, skeletal muscle, and the immune system. Polymorphic variants in the IL-6 gene influence IL-6 expression. We hypothesized that IL-6 alleles associate with increased serum of IL-6, decreased muscle strength, and frailty, and tested this in the Women's Health and Aging cohorts. We genotyped 463 participants age 70-79, and identified three common IL-6 haplotype blocks for the Caucasian (n=363) and African American (n=100) subsets. Using linear and logistic regression, and adjusting for age, BMI, race, and osteoarthritis, we identified no significant or clinically meaningful relationship between any single IL-6 single nucleotide polymorphism (SNP) or any IL-6 haplotype and serum IL-6 level, grip, knee, or hip strength, or frailty. Given that the promoter SNP (rs1800795) has been reported to influence IL-6 levels and health outcomes, we performed a similar association study in the In Chianti population (n=266) and confirmed lack of association. These results suggest that IL-6 gene variation may not be an important factor in the determination of elevated IL-6 levels and related phenotypes found in older women.