Introduction & Objective: Hundreds of common genetic variants have been associated with type 2 diabetes and glycated haemoglobin (HbA1c). However, the vast majority of these variants lie in regions of the genome which are not protein coding, making it difficult to identify biological pathways. We aimed to identify rare non-coding variants to aid in pinpointing causal genes and variants.
Methods: We performed a whole-genome sequencing association analysis of non-coding variation in 200,000 UK Biobank participants. We stratified our analysis by three genetically-inferred ancestries: European-like (EUR), African-like (AFR) and South Asian-like (SAS).
Results: We identified 4 rare (MAF<0.1%) variants associated with HbA1c, downstream of the haemoglobin alpha gene-cluster based on an analysis of EUR-like participants. In our analysis of 3,184 AFR-like individuals, only one variant (16:715289:T:C) showed evidence of replication. This likely-causal variant lies in the first element of the kozak sequence of meteorin (METRN), and was associated with substantially increased HbA1c levels (beta = 4.87mmol/mol [3.54, 6.21], P = 8.14e-13). We observed no evidence of association with common blood cell traits, circulating glucose, or haemoglobin. We replicated our result in the recently released additional 300,000 UKB WGS samples (beta = 6.02mmol/mol [4.83, 7.20], P = 2.93e-17). We attempted to replicate our findings in All of Us (N = 250,000), but found that the allele was substantially less frequent than in UKB (MAF = 3.7e-6 vs. 1.9e-4). The alternate allele was not present in individuals in TOPMed with HbA1c measures.
Conclusion: Our results suggest that this variant may be a founder effect in the UK population acting through an alteration of glucose uptake to red blood cells. Identification of a novel variant in only 200k individuals with whole-genome sequences suggests a high yield of novel variants and biological pathways from upcoming releases of millions whole-genomes.
G. Hawkes: None. K.A. Patel: None. I. Barroso: Stock/Shareholder; GlaxoSmithKline plc, NeoGenomics (NASDAQ: NEO). T.M. Frayling: None. A. Manning: None. M.N. Weedon: None.
Innovative Medicines Initiative 2 Joint Undertaking (875534)