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We present a whole-blood isoform ratio QTL (irQTL) resource by analyzing genome-wide isoform-to-gene expression ratios using sequencing data. In Framingham Heart Study (FHS, n  = 2622) discovery, we identify over 1.1 million cis -irQTLs (minor allele frequency [MAF] ≥ 0.01, ±1 Mb of 10,883 isoform transcripts, P  < 5 × 10 −8 ) across 4,971 genes. Among 11,425 sentinel cis -irQTLs, 72% replicate ( P  < 1 × 10 −4 ) in the Women’s Health Initiative (WHI; n  = 2005). Notably, 20% of cis -irQTLs have no significant association with overall gene expression, indicating isoform-specific regulation. These variants are enriched at splice donor/acceptor sites and genome-wide association study loci ( P  < 1 × 10 −10 ). We also identify 1870 sentinel trans -irQTLs (MAF ≥ 0.01, P  < 1.5 × 10 −13 ) for 1,084 isoforms across 590 genes, and 2327 rare cis -irQTLs (0.003 < MAF < 0.01) for 2467 isoforms of 1428 genes in FHS, with external replication rates of 61% and 41% in WHI, respectively. We highlight rs12898397 in ULK3 , which alters splice site usage and reduces expression of a full-length isoform. Mendelian randomization supports a causal role between this isoform shift and reduced diastolic blood pressure. These findings highlight the power of irQTL mapping to uncover transcript-specific regulatory mechanisms underlying complex traits. Here the authors use a genome-wide approach to identify genetic variants associated with RNA isoform variation, uncovering new links between transcriptional regulation and complex traits. The findings can advance understanding of disease mechanisms.

Background Substantial efforts have been dedicated to exploring the link between genetic regulation and the proteome, informing studies of complex trait mechanisms. Most of these efforts have been limited to populations of European ancestry. Results We conduct an Olink protein quantitative trait locus (pQTL) analysis on 1245 proteins involving 1033 self-identified African American (AA) and 1764 non-Hispanic White (NHW) participants from the Women’s Health Initiative and Framingham Heart Study. For replication of candidate pQTLs, we use data from 534 self-identified AA adults from the Jackson Heart Study and protein genome-wide association analysis statistics from the UK Biobank Pharma Proteomics Project, including 54,219 participants, of whom 931 are of African ancestry. In total, we identify and validate 5103 pQTLs (4496 or 88% cis- and 602 or 12% trans-pQTLs) for 983 proteins. Among these, 195 are previously unreported, with most (166 or 85%) identified in our AA sample, many of which were essentially monomorphic in European reference populations. Several of these newly identified African ancestry-specific pQTLs have been reported in ClinVar; our results suggest impact on circulating protein levels, potentially bolstering evidence for clinical significance. We identify a “cis pQTL hotspot” within the leukocyte receptor gene cluster on human chromosome 19q13.4. We also provide examples where a particular cis-pQTL, identified through conditional analysis, offers biological insights into an overlapping GWAS signal for disease susceptibility. Conclusions The identification of previously undescribed African ancestry-specific pQTLs contributes to understanding protein genetic regulation and highlights the significance of proteomic analysis in diverse populations.

Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population-specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328), Hispanic/Latino (22,379), Asian/Pacific Islander (8,640), and American Indian (653) and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease.

Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p  < 1E−7 where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs at p  < 1E−14 where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1191 clinical traits (enrichment FDR ≤ 0.05). Independent and external replication of the top 1000 significant cis and trans CpG-transcript pairs was completed in the Women’s Health Initiative and Jackson Heart Study cohorts. Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with cardiometabolic traits. In conclusion, we developed a robust and powerful resource of whole blood eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.

Background Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. Results We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance ( P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance ( P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. Conclusions Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.

Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The largest linkage peak was observed on chromosome 16p13 (MLOD = 2.81) for systolic blood pressure (SBP). Follow-up conditional linkage and association analyses in the linkage region identified multiple rare, coding variants in RBFOX1 associated with reduced SBP. In a 17-member CFS family, carriers of the missense variant rs149974858 are normotensive despite being obese (average BMI = 60 kg/m2). Gene-based association test of rare variants using SKAT-O showed significant association with SBP (p-value = 0.00403) and DBP (p-value = 0.0258) in the CFS participants and the association was replicated in large independent replication studies (N = 57,234, p-value = 0.013 for SBP, 0.0023 for PP). RBFOX1 is expressed in brain tissues, the atrial appendage and left ventricle in the heart, and in skeletal muscle tissues, organs/tissues which are potentially related to blood pressure. Our study showed that associations of rare variants could be efficiently detected using family information.

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10−7), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples (n = 5613 cases) or UK Biobank (n = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.

Background Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease. Methods Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets ( n  = 1,062,595). Results Carriers of 45 predicted damaging or loss-of-function CCR2 variants ( n  = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n  = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54–0.81, p  = 6.1 × 10 −5 ) and coronary artery disease (OR: 0.74, 95%CI: 0.63–0.87, p  = 2.9 × 10 −4 ) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers. Conclusions Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

We examined the association between HNF1B variants identified in a recent genome-wide association study and endometrial cancer in two large case-control studies nested in prospective cohorts: the Multiethnic Cohort Study (MEC) and the Women's Health Initiative (WHI) as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. A total of 1,357 incident cases of invasive endometrial cancer and 7,609 controls were included in the analysis (MEC: 426 cases/3,854 controls; WHI: 931 cases/3,755 controls). The majority of women in the WHI were European American, while the MEC included sizable numbers of African Americans, Japanese and Latinos. We estimated the odds ratios (ORs) per allele and 95% confidence intervals (CIs) of each SNP using unconditional logistic regression adjusting for age, body mass index, and four principal components of ancestry informative markers. The combined ORs were estimated using fixed effect models. Rs4430796 and rs7501939 were associated with endometrial cancer risk in MEC and WHI with no heterogeneity observed across racial/ethnic groups (P ≥ 0.21) or between studies (P ≥ 0.70). The OR(per allele) was 0.82 (95% CI: 0.75, 0.89; P = 5.63 × 10(-6)) for rs4430796 (G allele) and 0.79 (95% CI: 0.73, 0.87; P = 3.77 × 10(-7)) for rs7501939 (A allele). The associations with the risk of Type I and Type II tumors were similar (P ≥ 0.19). Adjustment for additional endometrial cancer risk factors such as parity, oral contraceptive use, menopausal hormone use, and smoking status had little effect on the results. In conclusion, HNF1B SNPs are associated with risk of endometrial cancer and that the associated relative risks are similar for Type I and Type II tumors.