Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWAS) of stroke, the second leading cause of death, have been conducted in populations of predominantly European ancestry.1,2 We undertook cross-ancestry GWAS meta-analyses of stroke and its subtypes in 110,182 stroke patients (33% non-European) and 1,503,898 control individuals of five ancestries from population- and clinic-based studies, nearly doubling the number of cases in previous stroke GWAS. We identified association signals at 89 independent loci, of which 61 were novel. Effect sizes were overall highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis using a novel machine-learning approach,3 transcriptome and proteome-wide association analyses revealed putative causal genes (e.g. SH3PXD2A and FURIN) and variants (e.g. at GRK5 and NOS3). Using a novel three-pronged approach,4 we provided genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWAS with vascular risk factor GWAS (iPGS) showed strong prediction of ischemic stroke risk in European and, for the first time, East-Asian populations.5,6 The iPGS performed better than stroke PGS alone and better than previous best iPGS, in Europeans and East-Asians. Transferability of European-specific iPGS to East-Asians was limited. Stroke genetic risk scores were predictive of ischemic stroke independent of clinical risk factors in 52,600 clinical trial participants with cardiometabolic disease and performed considerably better than previous scores, both in Europeans and East-Asians. Altogether our results provide critical insight to inform biology, reveal potential drug targets for intervention, and provide genetic risk prediction tools across ancestries for targeted prevention.

Genetic diversity patterns of human ethnic groups as inferred from the 1000 genomes

Human genetic diversity remains to be better understood. We here analyzed data from the 1000 Genomes Project and defined group specific fixed alleles (GSFAs) as those that are likely fixed in one ethnic group but non-fixed in at least one other group. The fraction of derived alleles in GSFAs indicates relative distance to apes because such alleles are absent in apes. Our results show that different groups differed in GSFA numbers consistent with known genetic diversity patterns, but also differed in the fraction of derived alleles in GSFAs throughout the entire genome, with East Asians having the largest fraction, followed by South Asians, Europeans, Native Americans, and Africans. Fast evolving sites such as intergenic regions were enriched with derived alleles and showed greater differences in GSFA numbers between East Asians and Africans. Furthermore, GSFAs in East Asians are mostly not fixed in other groups especially Africans, which was particularly more pronounced for fast evolving noncoding variants, while GSFAs in Africans are mostly also fixed in East Asians. Finally, variants that are likely non-neutral such as those leading to stop codon gain/loss and splice donor/acceptor gain/loss showed patterns similar to those of fast-evolving noncoding variants. These results can be accounted for by the maximum genetic diversity theory but not by the neutral theory or its inference that Eurasians suffered bottlenecks, and have implications for better management of group specific genetic diseases.

The Alcohol Flushing Response is Associated with the Risk of Depression

The alcohol flushing response is experienced by 36–45% of East Asians after drinking a small amount of alcohol. Since individuals with this response are incapable of metabolizing toxic acetaldehyde derived from alcohol effectively, this response is suggested as an indicator for the health risks associated with alcohol intake. Depression, a major health problem linked to alcohol consumption, might also be associated with the presence of the alcohol flushing response. Therefore, this study examined the association between the alcohol flushing response and the risk of depression in the general population of South Koreans. The analysis included 139,266 participants and used data from the 2019 Korean Community Health Survey. Only current drinkers were considered in the analysis. The relationship between the alcohol flushing response and depression was determined by logistic regression analysis using SAS 9.4. As a result, more than one-third of the population was found to be current flushers, and the relationship was significant among current flushers and depression (AOR=1.23, 95% CI 1.12–1.35, P-value=0.1ⅹ10-3) compared to never flushers. No association was found between former flushing response and depression. The odds of depression were significantly higher among alcohol flushers who drinks less than 15 g/day alcohol (<5 g/day: AOR=1.21, 95% CI=1.08-1.36, P-value=0.1ⅹ10-3; 5.0-14.9 g/day: AOR=1.40, 95% CI=1.14-1.71, P-value=0.1ⅹ10-3). In conclusion, this study reveals that a significant number of the South Korean population experiences the alcohol flushing response, and the individuals with the response are more likely to feel depressed, even with a small amount of alcohol consumption.

Investigating genetically mimicked effects of statins via HMGCR inhibition on immune-related diseases in men and women using Mendelian randomization

Statins have been suggested as a potential treatment for immune-related diseases. Conversely, statins might trigger auto-immune conditions. To clarify the role of statins in allergic diseases and auto-immune diseases, we conducted a Mendelian randomization (MR) study. Using established genetic instruments to mimic statins via 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition, we assessed the effects of statins on asthma, eczema, allergic rhinitis, rheumatoid arthritis (RA), psoriasis, type 1 diabetes, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn’s disease and ulcerative colitis in the largest available genome wide association studies (GWAS). Genetically mimicked effects of statins via HMGCR inhibition were not associated with any immune-related diseases in either study after correcting for multiple testing; however, they were positively associated with the risk of asthma in East Asians (odds ratio (OR) 2.05 per standard deviation (SD) decrease in low-density lipoprotein cholesterol (LDL-C), 95% confidence interval (CI) 1.20 to 3.52, p value 0.009). These associations did not differ by sex and were robust to sensitivity analysis. These findings suggested that genetically mimicked effects of statins via HMGCR inhibition have little effect on allergic diseases or auto-immune diseases. However, we cannot exclude the possibility that genetically mimicked effects of statins via HMGCR inhibition might increase the risk of asthma in East Asians.

Do East Asians With Normal Glucose Tolerance Have Worse β-Cell Function? A Meta-Analysis of Epidemiological Studies

BackgroundThe difference in the relationship between β-cell function and insulin resistance among Africans, Caucasians and East Asians with normal glucose tolerance (NGT) was not well investigated.MethodsWe searched PubMed and Web of Science with keywords and identified studies that used the homeostasis model assessment (HOMA) model to evaluate β-cell function (HOMA-B) and insulin sensitivity/resistance (HOMA-S/HOMA-IR) in certain ethnic groups. We used random-effect model to pool data of HOMAs and compared the combined data among the three ethnic groups using subgroup analysis. Linear regression analysis was used to estimate the coefficient of HOMA-S on HOMA-B in these ethnic groups.ResultsWe evaluated pooled data of HOMAs in eight African, 26 Caucasian, and 84 East Asian cohorts with NGT, and also 2,392, 6,645 and 67,317 individuals, respectively. The three ethnic groups had distinct HOMA-B but similar HOMA-IR. The regression coefficient of lnHOMA-B on lnHOMA-S was different between Africans and Caucasians (−1.126 vs −0.401, P = 0.0006) or East Asian (−1.126 vs −0.586, P = 0.0087), but similar between Caucasians and East Asians (−0.401 vs −0.586, P = 0.1282). The coefficient in all ethnic groups was similar when age, BMI, and gender were adjusted (African vs Caucasian P = 0.0885, African vs East Asian P = 0.1092, and Caucasian vs East Asian P = 0.6298).ConclusionsIn subjects with NGT, East Asians had lower HOMA-B but similar β-cell response relative to insulin resistance with Caucasians and Africans when age, BMI, and gender were controlled. This result may challenge the allegation that there was an Asian-specific diabetes phenotype with worse β-cell function.

Impact of Liability to Periodontitis on Glycemic Control and Type II Diabetes Risk: A Mendelian Randomization Study

While the association of periodontitis with Type II diabetes (T2DM) is well-established, the causal relationship remains uncertain. We examined the causal association of periodontitis with glycemic traits (HbA1c, fasting glucose, and fasting insulin) and T2DM using Mendelian randomization (MR) taking advantage of large genome-wide association studies of European and East Asian adults, i.e., the UK Biobank (n ≈ 350,000) (HbA1c), trans-ancestral MAGIC (HbA1c, fasting glucose, and insulin), and DIAMANTE (74,124 cases/824,006 controls), and AGEN for T2DM in Europeans and East Asians, respectively. Periodontitis was instrumented using single-nucleotide polymorphisms (SNPs), strongly and independently predicting liability to periodontitis in each ancestry group. SNP-specific Wald estimates were combined using inverse variance weighting. Sensitivity analyses were performed using the weighted median and MR-Egger with meta-analysis of MR estimates for Europeans and East Asians. Genetically instrumented liability to periodontitis was not associated with glycemic traits or T2DM in either ancestry or when ancestry specific estimates were meta-analyzed. Our findings do not support a causal association of liability to periodontitis with glycemic traits or T2DM. However, further research is required confirming these findings among other racial/ethnic groups, especially groups who carry a heavy burden of both periodontitis and T2DM.