<b>Clonal Hematopoiesis of Indeterminate Potential (CHIP) and incident type 2 diabetes (T2D) risk</b>

Objective: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident T2D is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.Research Design and Methods: CHIP was derived from whole genome sequencing of blood DNA in NHLBI Trans-omics for Precision Medicine (TOPMed) prospective cohorts. We analyzed 17,637 participants from 6 cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP vs. no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios and 95% confidence intervals (HR [CI]) adjusted for age, sex, body mass index, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts’ estimates via fixed effects meta-analysis.Results: Mean age was 63.4 years (SD=11.5), 76% were female, and CHIP prevalence was 6.0% (n=1,055) at baseline. T2D was diagnosed in n=2,467 over mean follow-up of 9.8 years. Participants with CHIP had a 23% (1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, TET2 (HR=1.48; 1.05, 2.08) and ASXL1 (HR=1.76; 1.03, 2.99) mutations were at higher T2D risk, and DNMT3A was non-significant (HR=1.15; 0.93, 1.43); statistical power was limited for JAK2 and TP53 analyses.Conclusions: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.</p

Additional file 1 of Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Additional file 1: Supplemental Text. Table S1. Sample size and the number of SNPs in the paragraph delayed recall GWAS from each discovery and replication cohort. Table S2. Sample size and the number of SNPs in the word list delayed recall GWAS from each discovery and replication cohort. Table S3. Tissue-specific relationships between delayed recall test (PAR-dr and WL-dr) summary SNP associations and eQTLs and meQTLs. Table S4. Relationship Between Delayed Recall Summary Gene Associations and Transcription Factor Genes. Table S5. Significant Genes Associated with Paragraph Delayed Recall (PAR-dr) and Word List Delayed Recall (WL-dr). Table S6. Significant component genes in the six memory-associated pathways. Table S7. Homologous genes in memory-associated pathways for differential expression analysis. Figure S1. GWAS cohorts and microarray expression datasets. Figure S2. Design of the pathway analyses. Figure S3. Forest plots of significant pathway enrichment effects and p-values from discovery cohorts (Approach 1)

Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects

Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ~4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes