Guanjie Chen

Aims/hypothesis: Evidence for a causal role of DNA methylation sites (CpGs) in type 2 diabetes and glycaemic traits is limited due to the cross-sectional nature of many epigenome-wide association studies (EWAS). In addition, epigenetic studies in West African populations are particularly sparse, despite the high and rising burden of type 2 diabetes in these populations. Hence, we aimed to identify CpGs causally associated with type 2 diabetes among West Africans by leveraging Mendelian randomisation (MR) analysis and longitudinal data. Methods: We used the Illumina EPIC DNA methylation array to profile the methylation of DNA extracted from white blood cells collected from 879 Ghanaian individuals (the Research on Obesity and Diabetes among African Migrants [RODAM] study) and 332 Nigerian individuals (the Africa America Diabetes Mellitus [AADM] study) who were not on glucose-lowering medication. We carried forwards CpGs identified in EWAS for type 2 diabetes and meta-analysed EWAS for HbA _1c and homeostatic model assessment estimates of insulin sensitivity (HOMA-S) as exposures to two-sample MR analysis. Independent cis methylation quantitative trait loci (meQTLs) were calculated using methylation data from blood and primary hepatocytes and subsequently used as instrumental variables (SNP–exposure associations). Genome-wide association analyses for type 2 diabetes on 4120 participants from the AADM study were used to derive the SNP–outcome associations. Longitudinal trait data ( n =138) and RNA-seq data ( n =77 blood, 49 adipose, 55 muscle) available for a subset of Nigerians were used for follow-up analyses. Results: We identified 28 CpGs associated with type 2 diabetes, 26 with HbA _1c and three with HOMA-S (total CpGs: 57), of which 49 had meQTLs in blood (AADM study data) and four had meQTLs in primary hepatocytes from African American individuals. MR analysis provided evidence for causality for cg00036588 and cg16759041 in type 2 diabetes using blood and hepatocyte meQTLs, respectively. Longitudinal analyses showed an association between baseline methylation of these CpGs with HbA _1c at follow-up. RNA-seq data revealed a cis correlation of cg00036588 with FAM83C (false discovery rate [FDR]=3.3 × 10 ^–4 ) and EIF6 (FDR=0.13) in skeletal muscle. Conclusions/interpretation: Our study identified two epigenetic markers as likely to be causal for type 2 diabetes in West African populations. In addition to enhancing our understanding of disease mechanisms, these CpGs with evidence of causal associations could be prioritised as potential biomarkers for early detection of disease or as drug development targets.

Genetic predisposition and alcohol consumption are risk factors for increased blood pressure (BP), but their interactions influencing BP remain understudied. We conducted population-specific and cross-population meta-analyses of genome-wide gene-alcohol (GxAlc) interactions affecting BP in >1.1M individuals from multiple populations. We identified 46 GxAlc interaction loci for BP, including 21 from one-degree-of-freedom interaction tests (PGxAlc<5x10-8; or <0.05/Meff, Meff independent BP associations at P<10-5), and 25 from two-degree-of-freedom tests of main and interaction effects (PGxAlc<0.05/M2df, M2df independent 2df-associations at P2df<5x10-8), including 7 novel and 39 known BP loci. The 12q24 locus highlights the genetic effect of BRAP-rs11066001 on BP, being ~6 times larger in current drinkers than in non-drinkers. Gene prioritization with 46 GxAlc loci identified 15 genes with ≥3 lines of evidence (location, literature, druggability, functional/regulatory annotation, or pathway analyses). Several loci showed sex- and population-specific effects and revealed biological pathways of alcohol’s influence on BP, suggesting mechanisms underlying alcohol-induced hypertension.

Kidney disease disproportionately affects populations of African ancestry, yet most genetic studies have focused on Europeans. Here, we present a three-stage genome-wide association study meta-analysis of estimated glomerular filtration rate in ~26,000 individuals across Eastern, Western, and Southern Africa and ~81,000 African-ancestry individuals in the diaspora. Continental African meta-analysis identifies four independent genome-wide significant loci, including two previously unreported loci. Pan-African meta-analysis identifies 19 independent loci, including three previously unreported loci. Fine-mapping reveals four loci with high causality probability, and phenome-wide analyses demonstrate pleiotropic effects on cardiometabolic and immunological traits. Notably, APOL1 high-risk variants strongly associated with kidney disease in African Americans show markedly lower frequency and attenuated effects in continental Africa, indicating potential distinct genetic architectures. Polygenic scores from genetically similar populations significantly outperformed those from distant cohorts. These findings demonstrate the necessity of conducting genomic research across diverse African populations to enable equitable health outcomes.

The study investigates host genetic factors influencing COVID-19 susceptibility by integrating WGS, epigenomics, and transcriptomic data. It identified that PMF1 is linked to COVID-19. Mediation analysis revealed that genetic variants in PMF1 affect COVID-19 status via combinations of one transcript (annotated to GLMP) and three DNAm sites (annotated to ARHGEF2, TMEM79, MEX3A). The findings highlight the role of lysosomal pathways and transmembrane proteins in disease susceptibility, offering new insight into potential therapeutic targets for COVID-19.

Liver enzymes are critical biomarkers of hepatic metabolism, injury, and systemic homeostasis. Their genetic architecture remains understudied in African-ancestry populations. We addressed this knowledge gap by conducting genome-wide analyses of four liver enzymes in over 55,000 individuals of African ancestry from six cohorts across sub-Saharan Africa, the United States, and the United Kingdom. We identified 31 significant loci, of which 14 were novel, including TMEM64 and CRYL1 for alkaline phosphatase, IMMP2L for alanine aminotransferase, and PDE4D for gamma-glutamyl transferase. Several novel variants exhibited high allele frequencies in African-ancestry populations but were rare or absent in other global populations. Functional annotation indicated that lead variants overlapped liver-active regulatory regions, histone marks, and hepatocyte eQTLs. Colocalization and enrichment analyses implicated pathways related to lipid and carbohydrate metabolism, glycosylation, and immune function. Our findings expand the catalog of genetic variants influencing liver enzymes and advance understanding of the biological mechanisms underlying liver function.

Conventional genome‐wide association studies (GWAS) are designed to assess the effect of a genetic locus on phenotypic mean by genotype. Such loci explain a proportion of phenotypic variance known as narrow‐sense heritability. In contrast, variance quantitative trait loci (vQTL) are associated with the phenotypic variance by genotype. These loci explain an additional proportion of phenotypic variance and contribute to broad‐sense heritability but not to narrow‐sense heritability. Here, a genome‐wide vQTL analysis in 22,805 African Americans yielded eight loci for body mass index (BMI). Of these loci, three were replicated in 6002 sub‐Saharan Africans. No locus reached genome‐wide significance using the standard additive model. Furthermore, no locus showed evidence for natural selection, haplotype effects, or gene × sex or gene × study interactions. Two loci showed evidence for an effect of locus‐specific ancestry resulting from admixture and for a gene × gene interaction. One locus showed evidence for interaction with diastolic blood pressure, consistent with this vQTL capturing an unmodeled gene × covariate interaction. These analyses demonstrate that relevant BMI loci can be detected by evaluating vQTL and that these loci contribute to the underexplored broad‐sense heritability for this trait.

Background: Kidney disease is more prevalent in populations of African ancestry, yet most genome-wide association studies (GWAS) for kidney function markers have been performed in Europeans. To discover additional loci in individuals of African ancestry, we assembled 10 GWASs of the estimated glomerular filtration rate (eGFR) across diverse African regions, including ~26,000 individuals as part of the newly established KidneyGenAfrica consortium. Additional GWASs of eGFR in ~81,000 African-ancestry individuals in the diaspora were aggregated from the Million Veteran Program (MVP), UK Biobank (UKBB), and the Chronic Kidney Disease Genetics (CKDGen) Consortium. Methods: We performed a three-stage GWAS meta-analysis: (1) Three regional meta-analyses in eastern, western, and southern Africa; (2) a continental African meta-analysis; and (3) a pan-African meta-analysis pooling continental and diaspora studies. We performed fine-mapping, colocalization, functional annotation using MAGMA/FUMA, and a phenome-wide association study (PheWAS). We investigated the role of APOL1 haplotypes in low eGFR in continental Africa. Polygenic scores (PGSs) were estimated from regional, continental, pan-African, and multi-ancestry meta-analyses in a Malawi MEIRU cohort divided into testing and validation sets. Results: The regional meta-analyses identified 28 genome-wide significant loci, including 5 novel loci at FAM72C, LOC645752 , OPRM1 , KLH1 , and LAMA4 . The pan-African meta-analysis detected 20 independent loci, including four novel loci (ARG 1 , OR52H1 , TRIM69 , and SQRDL ). Our fine-mappingidentified four loci with a posterior probability of causality > 0.99. Colocalization recapitulated known eGFR-related genes, and PheWAS showed a pleiotropic profile for 23 of the identified loci, particularly with cardiometabolic, immunological, dermatological, nutritional, and psychiatric traits. The overall APOL1 high-risk haplotype frequency in continental Africa was 5%, significantly lower than the approximately 13% observed in African Americans. Notably, we found a limited association between APOL1 variants and low eGFR in continental Africa, which contrasts with the strong APOL1 association with chronic kidney disease observed in African Americans, highlighting distinct genetic risk profiles for kidney disease between African populations and African Americans. PGSs derived from southern African datasets outperformed those from other regional, continental, and multi-ancestry-derived PGSs in the Malawi cohort. Conclusion: We identified novel loci associated with eGFR in individuals of African ancestry from the largest GWAS of eGFR conducted in Africa to date. We observed potential distinct genetic factors that may influence eGFR in continental Africans and African Americans. This suggests that other genetic factors may play a more significant role in eGFR risk among continental Africans. PGSs derived from close genetic distance with discovery cohorts performed better than PGSs derived from other regions, including multi-ancestry data.

Background: Sex is a crucial factor in the development, progression, and treatment of cancer, making it vital to examine cancer incidence trends by sex for effective prevention strategies. Objective: This study aimed to assess the incidence of cancer in China between 2007 and 2021, with a focus on sex-based trends. Methods: A population-based cancer registry comprising 14.14 million individuals was maintained between 2007 and 2021 by the Beijing Municipal Health Big Data and Policy Research Center. The age-standardized rates (ASRs) of cancers were calculated using the Segi population. The average annual percentage of change (AAPC) was evaluated using the joinpoint regression model, while the Bayesian age-period-cohort model was used to predict cancer incidence in the next 10 years. Results: From 2007 to 2021, the study included 651,342 incident patients with cancer, of whom 51.2% (n=333,577) were women. The incidence indicated by the ASR for all cancers combined was 200.8 per 100,000 for women and 184.4 per 100,000 for men. The increase in incidence indicated by AAPC for all malignancies combined significantly increased in women between 2007 and 2021 (AAPC=3.1%; P<.001), whereas it remained constant in men (AAPC=0.3%; P=.30). Although the overall incidence of all cancers indicated by AAPC increased in young men (AAPC=3.2%; P=.01), the greatest increase was observed among young women (AAPC=6.1%; P<.001). The incidence rate ratio for cancer in women increased among subsequent younger generations compared with patients born in the 1962-1966 cohort. The ASR in women will increase 1.6-fold over the next 10 years, with women having twice the incidence rate of men by 2031. Conclusions: The rising incidence of cancer among women in China has become a growing concern, emphasizing the need for increased efforts in cancer prevention and early screening, especially among young women.

BACKGROUND Sex is a crucial factor in the development, progression, and treatment of cancer, making it vital to examine cancer incidence trends by sex for effective prevention strategies. OBJECTIVE This study aimed to assess the incidence of cancer in China between 2007 and 2021, with a focus on sex-based trends. METHODS A population-based cancer registry comprising 14.14 million individuals was maintained between 2007 and 2021 by the Beijing Municipal Health Big Data and Policy Research Center. The age-standardized rates (ASRs) of cancers were calculated using the Segi population. The average annual percentage of change (AAPC) was evaluated using the joinpoint regression model, while the Bayesian age-period-cohort model was used to predict cancer incidence in the next 10 years. RESULTS From 2007 to 2021, the study included 651,342 incident patients with cancer, of whom 51.2% (n=333,577) were women. The incidence indicated by the ASR for all cancers combined was 200.8 per 100,000 for women and 184.4 per 100,000 for men. The increase in incidence indicated by AAPC for all malignancies combined significantly increased in women between 2007 and 2021 (AAPC=3.1%; P<.001), whereas it remained constant in men (AAPC=0.3%; P=.30). Although the overall incidence of all cancers indicated by AAPC increased in young men (AAPC=3.2%; P=.01), the greatest increase was observed among young women (AAPC=6.1%; P<.001). The incidence rate ratio for cancer in women increased among subsequent younger generations compared with patients born in the 1962-1966 cohort. The ASR in women will increase 1.6-fold over the next 10 years, with women having twice the incidence rate of men by 2031. CONCLUSIONS The rising incidence of cancer among women in China has become a growing concern, emphasizing the need for increased efforts in cancer prevention and early screening, especially among young women.

Objective: The purpose of this study was to evaluate the effectiveness of post-traumatic growth (PTG) model-based intervention to improve positive psychological traits in Chinese breast cancer patients. Design: A randomized control trial of a psychological group intervention based on PTG model. Methods: The Clinical Trial was registered on 17 August 2019 at Chinese Clinical Trials.gov with Registration number ChiCTR1900025264. A total of 92 patients with breast cancer were recruited. The participants were randomly assigned to the experimental group (n = 46) and the control group (n = 46). A six-session psychological group intervention based on PTG model was implemented in the experimental group, and a six-session health education was implemented in the control group. The outcomes were measured at baseline (pre-intervention), 3 weeks, 6 weeks after the intervention. The primary outcome was posttraumatic growth assessed by the Chinese version of the Post-Traumatic Growth Inventory (PTGI); Secondary outcomes included psychological resilience, family resilience, rumination, and self-disclosure. Results: A total of 87 patients with breast cancer completed this study, including 44 patients in the experimental group and 43 patients in the control group. There was no significant difference in baseline data of breast cancer patients between the two groups except for the treatment regimen (p > 0.05). The two groups were compared after the intervention; the interaction effects between the total scores of posttraumatic growth, family resilience, and self-disclosure and the time term were statistically significant (p < 0.05), indicating that the trend of change in total scores of post-traumatic growth, family resilience, and self-disclosure differed between the experimental and control groups over time, and the scores improved in the experimental group were significantly higher than those in the control group. The comparison of psychological resilience and total score of rumination at each time point was statistically significant (p < 0.05), indicating that group intervention based on the PTG model could improve the psychological recovery ability and rumination level of the experimental group. Conclusion: The psychological group intervention based on the PTG model significantly improved post-traumatic growth, family resilience, and self-disclosure in patients with breast cancer. However, the impact on psychological resilience and rumination was relatively small. Long-term intervention is needed to further test the effect of the PTG model on psychological resilience and rumination.