Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Family-based investigation of the genetics and epigenetics of obesity in Qatar

Single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and DNA methylation patterns play a role in the susceptibility to obesity. Despite the alarming figures of obesity in the Arab world, the genetics of obesity remain understudied in Arabs. Here, I recruited ten multigenerational Qatari families segregating obesity, and generated genome-wide SNP genotyping, whole genome sequencing and genome-wide methylation profiling data using Illumina platforms to investigate the role of rare mutations, CNVs, and DNA methylation patterns in the susceptibility to obesity. For the identification of obesity mutations, I first identified candidate obesity regions through linkage and run of homozygosity analyses, and then investigated these regions to detect potential deleterious mutations. These analyses highlighted putative rare variants for obesity risk at PCSK1, NMUR2, CLOCK and RETSAT. The functional impact of the PCSK1 mutation on obesity was previously demonstrated while for the other candidates further work is needed to confirm their impact. For the identification of common obesity CNVs, I performed a genome-wide CNV association analysis with BMI and identified a common duplication of ~5.6kb on 19p13.3 that associates with higher BMI. Moreover, I investigated large (≥500kb) rare CNVs and identified a ~618kb deletion on 16p11.2 in the most extremely obese subject in my samples, which confirms the contribution of the previously reported 16p11.2 deletions to severe obesity beyond European populations. For the identification of DNA methylation changes in obesity, I attempted to replicate known associations with BMI from large EWASs. I replicated the associations at ABCG1 (P-value=6.3X10-3) and CPT1A (P-value=8.7X10-5) and compared the effects observed to the TwinsUK cohort through a meta-analysis. I observed low heterogeneity between the two studies, and that increased the associations at ABCG1 (P-value=2.5x10-13) and CPT1A (P-value=1.9x10-15). In conclusion, the work represents the first genetic and epigenetic study of obesity in an Arab population. I replicated known genetic and epigenetic obesity susceptibility loci and also discovered novel potential loci.Open Acces

Prevalence of At-Risk Marriages among Couples Attending Premarital Screening (PMS) Programs: A Systematic Review and Meta-Analysis

Background: Hemoglobinopathies are among the most common inherited genetic diseases. The World Health Organization estimates that at least 5% of the world's population are carriers for hemoglobinopathies (2.9% for thalassemia and 2.3% for sickle cell disease). Programs like Premarital Screening (PMS) have been developed in most Middle East countries on a mandatory basis to reduce at-risk marriages by providing counseling after a confirmed 'genetic carrier' state for hemoglobinopathies. Aim/Objective: The aim of this systematic review and meta-analysis was to estimate the prevalence of at-risk marriages globally and see the variation by region, income level, ethnicity, study period, implementation year of PMS program, study design and consanguinity proportion. Methods: Different databases such as PubMed, Science Direct, and Scopus were searched systematically by using key terms and MeSH Terms. Studies from Google Scholar and reference lists of studies were also collected, and the author extracted all relevant data. Two reviewers independently conducted quality assessment by using Hoy et al (2012) risk of bias tool. Quality effects model (QEM) was used due to considerable heterogeneity observed between studies. Subgroup analysis and sensitivity analysis were also performed for assessing the causes of heterogeneity. Results: A total of 15 studies were included in this meta-analysis. The overall pooled prevalence of at-risk marriages among total couples at-risk was 64% (95% CI: 49%- 78%). Estimates of several subgroups were found to be different as compared to the overall pooled estimate. Funnel plot and Doi plot indicated the presence of publication bias. Sensitivity analysis including only studies with low risk led to a pooled estimate of 52% (CI: 46%, 57%) and indicated absence of publication bias. Conclusion and Recommendations: The pooled estimates varied widely and there was a substantial heterogeneity among studies, therefore, there is a need for more well-designed studies across different countries. Moreover, the importance of the quality of counseling sessions should be stressed and combined with efforts in other community sectors, such as high schools where students can attain high knowledge regarding genetic diseases before the age of marriag

A population study of clinically actionable genetic variation affecting drug response from the Middle East

Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond. 2022, The Author(s).PVJ is supported by faculty funding from the College of Health & Life Sciences, HBKU. Qatar Biobank and Qatar Genome Program are Research, Development & Innovation's entities within Qatar Foundation for Education, Science and Community Development. Funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.Scopu

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272AbstractLung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.</jats:p