Objective: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P 100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.

Background: In mice, GPR146 (G-protein–coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. Methods: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK Biobank. The Lifelines, The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. Results: In the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease ( P =0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. Conclusions: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.

SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the SLC5A2 gene or within 25kb of the 5′ and 3′ flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and SLC5A2 expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5′ or 3′ prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to SLC5A2. In conclusion, no genetic variant was found mimicking SGLT2i based on their location near SLC5A2 and their association with sodium excretion or HbA1c and SLC5A2 expression or function.

Human populations differ in disease prevalence and phenotypes, but the extent to which differences are caused by genetic factors is unknown for most complex traits. Comparing phenotypic means across populations is confounded by environmental differences and using polygenic predictors can lead to biased inference ^1,2 . Family-based analyses of people of genetically admixed ancestry enable estimation of ancestry effects unconfounded by ancestry–environment correlations. Here we leverage genetic data from admixed adults in the Mexico City Prospective Study ^3,4 to estimate within-family ancestry effects ⁵ . We assessed genetic ancestry and 15 complex traits in 52,583 unrelated people and 39,714 relatives from 17,627 families. At the population level, relative to European ancestry, the effect of Indigenous American ancestry was −1.98 s.d. ( P < 2 × 10 ⁻¹⁶ ) for height and a natural log odds ratio of 1.73 (95% confidence interval, 1.54–1.92) for type 2 diabetes. Within families, the effect of Indigenous American ancestry was −1.51 s.d. ( P = 10 ⁻⁸ ) for height and natural log odds ratio of 5.13 (95% confidence interval, 2.48–7.78) for type 2 diabetes. These effects are supported by between-ancestry differences in trait-increasing allele counts and evidence of selection at trait-associated loci. We found no within-family ancestry effect on educational attainment or other traits despite significant associations at the population level, implying environmental causes or confounding. Overall, this study provides an experimental design to study between-ancestry genetic effects and identifies significant ancestry differences for height, type 2 diabetes and metabolic traits in a genetically diverse population from Mexico City.