Cohort Profile: East London Genes & Health (ELGH), a community based population genomics and health study of British-Bangladeshi and British-Pakistani people

Abstract

Why was the cohort set up?East London Genes & Health (ELGH) is a community based, long-term study of health and disease in British-Bangladeshi and British-Pakistani people in east London. ELGH has a population-based design incorporating cutting-edge genomics with electronic health record (EHR) data linkage and targeted recall-by-genotype (RbG) studies. ELGH currently has >34,000 volunteers with funding to expand to 100,000 volunteers by 2023. ELGH is an open access data resource, and its research will impact a population at high need and redress the poor representation of non-White ethnic groups in existing population genomic cohorts 1 .Almost a quarter of the world's population, and 5% of the UK population, are of South Asian origin 2 .The risk of coronary heart disease is 3-4 times higher, and type 2 diabetes (T2D) 2-4 times higher in UK South Asians compared with Europeans 3,4 . East London incorporates one of the UK's largest South Asian communities (29% of 1.95 million people), of which 70% are British-Bangladeshi and British-Pakistani, and its population live in high levels of deprivation (Tower Hamlets, Hackney, Barking and Dagenham are the 9 th , 10 th and 11 th most deprived local authorities in England) 5 . Compared to White Europeans, South Asians living in east London have a two-fold greater risk of developing T2D 6 , nearly double the risk of non-alcoholic liver disease 7 , and over double the risk of multimorbidity 8 , with the onset of cardiovascular disease occurring 8 years earlier in men 8 . Determinants of poor cardiometabolic health start early in the life course, with higher rates of overweight and obese children in east London compared to the UK average 5 .Recent genomic advances offer exciting potential to better understand the genetic causation of disease 9 , and to direct pharmacotherapy to rare loss-of-function gene variants 10 . Genetic variation relevant to British-Bangladeshi and British-Pakistani populations, such as autozygosity arising from parental relatedness, is under-researched with regards to potential effects on complex adult phenotypes at a population level 11,12 .ELGH fosters authentic, inclusive, long-term engagement in its research, to deliver future health benefits to the population it represents. Community involvement in ELGH helps prioritise areas for

Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank

“…While the number of genes with heterozygous instances of LOF variants is approaching saturation at this sample size, exome sequencing of the entirety of the UKB resource will dramatically increase the number of LOF carriers and the ability to detect phenotypic associations. We also observe 1,071 autosomal genes with homozygous instances of rare LOF variants, and this number of genes will also increase with continued sequencing of all UKB participants; however, studies in populations with a high degree of parental relatedness 50,51 will provide yet more genes with homozygous LOFs and complement efforts such as UKB. LOF variation is an extremely important class of variation for identifying drivers of high genetic risk, novel disease genes, and therapeutic targets.…”

Evaluating potential drug targets through human loss-of-function genetic variation

“…Unlike in bottlenecked populations, where certain pLoF variants can be very common, the allele frequency of pLoF variants is not shifted in populations with elevated rates of consanguinity; only the homozygote frequency is dramatically shifted to the right ( Figure 4C). These properties explain why the study of these populations has been highly fruitful to date 53,57,58 and justify ambitious plans to expand these cohorts in the coming years 56,59 . However, it is worth emphasizing that because the underlying variants are still rare, studying these populations may only identify a handful of individuals with a homozygous pLoF genotype in a specific gene of interest; such data may be adequate to address safety questions and identify stark phenotypic effects 53 , but will often be highly underpowered for the study of subtle clinical phenotypes or the direct validation of disease-protective effects.…”

“…The study of consanguineous individuals, by contrast, is much more likely to identify homozygous pLoF genotypes for a pre-determined gene of interest. The East London Genes & Health (ELGH) initiative 56 has recruited ~35,000 British Pakistani and Bangladeshi individuals, about 20% of whom report that their parents are related. On average, the N=2,912 individuals who reported that their parents were second cousins or closer had 5.8% (about 1/17 th ) of their genome in runs of autozygosity, meaning that both chromosomes are identical, inherited from the same recent ancestor.…”

Implementation of public health genomics in Pakistan

“…The East London Genes & Health (ELGH) study investigates the health of British-Bangladeshi and British-Pakistani populations in East London, UK. ELGH has already recruited over 30,000 participants and aims to recruit 100,000 participants by 2023 [58]. To date, 9681 (33%) of the ELGH participants have been British-Pakistani.…”

“…By 2023, 100,000 participants will have their whole exome sequenced. The ELGH project can link genomic data with real time electronic health record data, and perform recall-bygenotype studies, with associated follow-up in the future [58].…”