Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

Background: The current study explores the genetic underpinnings of cardiac arrhythmia phenotypes within Middle Eastern populations, which are under-represented in genomic medicine research. Methods: Whole-genome sequencing data from 14,259 individuals from the Qatar Biobank were used and contained 47.8% of Arab ancestry, 18.4% of South Asian ancestry, and 4.6% of African ancestry. The frequency of rare functional variants within a set of 410 candidate genes for cardiac arrhythmias was assessed. Polygenic risk score (PRS) performance for atrial fibrillation (AF) prediction was evaluated. Results: This study identified 1196 rare functional variants, including 162 previously linked to arrhythmia phenotypes, with varying frequencies across Arab, South Asian, and African ancestries. Of these, 137 variants met the pathogenic or likely pathogenic (P/LP) criteria according to ACMG guidelines. Of these, 91 were in ACMG actionable genes and were present in 1030 individuals (~7%). Ten P/LP variants showed significant associations with atrial fibrillation p < 2.4 x 10-10. Five out of ten existing PRSs were significantly associated with AF (e.g., PGS000727, p = 0.03, OR = 1.43 [1.03, 1.97]). Conclusions: Our study is the largest to study the genetic predisposition to arrhythmia phenotypes in the Middle East using whole-genome sequence data. It underscores the importance of including diverse populations in genomic investigations to elucidate the genetic landscape of cardiac arrhythmias and mitigate health disparities in genomic medicine.This publication was made possible by the PPM3 award PPM 03-0322-190036 from the Qatar National Research Fund (QNRF, a member of the Qatar Foundation).Scopu

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

Qatar Biobank Cohort Study: Study Design and First Results.

The authors describe the design, implementation and results of Qatar Biobank (QBB) for the first 10,000 participants. QBB is a prospective population-based cohort study in Qatar, established in 2012. QBB's primary goal was to establish a cohort accessible to the local and international scientific community providing adequate health data and biological samples enabling evidence-based research. The study design is based on an agnostic hypothesis, collecting data using questionnaires, biological samples, imaging data and omics. QBB aims to recruit 60,000 participants, men and women, adult (age ≥ 18 years) Qataris or long-term residents (≥ 15 years living in Qatar) and follow up with them every 5 years. Currently, QBB has reached the 28% (n=17,065) of the targeted population and more than 2 million biological samples. QBB is a multinational cohort including 33 different nationalities with a relatively young population (mean age, 40.5 years), highly educated (50% university-educated) with high monthly incomes. The four main non-communicable diseases found among QBB population are Dyslipidemia, Diabetes, Hypertension and Asthma with a 30%, 17.3%, 16.7% and 9% prevalence, respectively. QBB repository can provide data and biological samples sufficient to demonstrate valid associations between the genetic and/or environmental exposure and disease development to the scientists worldwide

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

Background: The current study explores the genetic underpinnings of cardiac arrhythmia phenotypes within Middle Eastern populations, which are under-represented in genomic medicine research. Methods: Whole-genome sequencing data from 14,259 individuals from the Qatar Biobank were used and contained 47.8% of Arab ancestry, 18.4% of South Asian ancestry, and 4.6% of African ancestry. The frequency of rare functional variants within a set of 410 candidate genes for cardiac arrhythmias was assessed. Polygenic risk score (PRS) performance for atrial fibrillation (AF) prediction was evaluated. Results: This study identified 1196 rare functional variants, including 162 previously linked to arrhythmia phenotypes, with varying frequencies across Arab, South Asian, and African ancestries. Of these, 137 variants met the pathogenic or likely pathogenic (P/LP) criteria according to ACMG guidelines. Of these, 91 were in ACMG actionable genes and were present in 1030 individuals (~7%). Ten P/LP variants showed significant associations with atrial fibrillation p −10. Five out of ten existing PRSs were significantly associated with AF (e.g., PGS000727, p = 0.03, OR = 1.43 [1.03, 1.97]). Conclusions: Our study is the largest to study the genetic predisposition to arrhythmia phenotypes in the Middle East using whole-genome sequence data. It underscores the importance of including diverse populations in genomic investigations to elucidate the genetic landscape of cardiac arrhythmias and mitigate health disparities in genomic medicine

The QChip1 knowledgebase and microarray for precision medicine in Qatar

Risk genes for Mendelian (single-gene) disorders (SGDs) are consistent across populations, but pathogenic risk variants that cause SGDs are typically population-private. The goal was to develop "QChip1," an inexpensive genotyping microarray to comprehensively screen newborns, couples, and patients for SGD risk variants in Qatar, a small nation on the Arabian Peninsula with a high degree of consanguinity. Over 108 variants in 8445 Qatari were identified for inclusion in a genotyping array containing 165,695 probes for 83,542 known and potentially pathogenic variants in 3438 SGDs. QChip1 had a concordance with whole-genome sequencing of 99.1%. Testing of QChip1 with 2707 Qatari genomes identified 32,674 risk variants, an average of 134 pathogenic alleles per Qatari genome. The most common pathogenic variants were those causing homocystinuria (1.12% risk allele frequency), and Stargardt disease (2.07%). The majority (85%) of Qatari SGD pathogenic variants were not present in Western populations such as European American, South Asian American, and African American in New York City and European and Afro-Caribbean in Puerto Rico; and only 50% were observed in a broad collection of data across the Greater Middle East including Kuwait, Iran, and United Arab Emirates. This study demonstrates the feasibility of developing accurate screening tools to identify SGD risk variants in understudied populations, and the need for ancestry-specific SGD screening tools. 2022, The Author(s).This is a collaborative work between Qatar Genome, Qatar Biobank, Weill Cornell (New York and Qatar), Hamad Medical Corporation and Sidra Medicine. We are thankful for everyone who contributed to this endeavor from all participating institutes. We would like to especially thank all participants in this study for their continuous support. We thank Dr. Fatemeh Abbaszadeh, for quality control and implementing QChip in the diagnostic services; N. Mohamed for editorial support, E. Betancourt for administrative support, E. Guzman for IT support, and J. Pillardy for high-performance computing support. J.R.F. also thanks Alan R. Shuldiner and Regeneron Genetics Center for supporting, J.R.F. to help complete this project. Special thanks to Alphonse Tharangeval at the Dasman Diabetes Institute in Kuwait for providing allele frequency lookups, and to the Center for Arab Genetic Studies in UAE, the GME Variome at University of California at San Diego and the Iranomefor providing public access to their databases. The authors are saddened by the passing of Andrew Brooks after the manuscript was submitted to the journal for review. This publication was made possible by The Qatar Foundation, the Weill Cornell Medical College in Qatar; NPRP 09-741-3 193, NPRP 5-436-3-116, NPRP 7-1425-3-370, NPRP 7-1301-3-336, and NPRP P8-1913-3-396 from the Qatar National Research Fund (a member of the Qatar Foundation). The findings achieved herein are solely the responsibility of the authors.Scopu

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