LncRNA-Associated Genetic Etiologies Are Shared between Type 2 Diabetes and Cancers in the UAE Population

SIMPLE SUMMARY: The genome-wide association study (GWAS) approach to common human disease relies on single nucleotide polymorphisms (SNPs), the most common type of genetic variation in the human genome, and distinguishes “risk” and “healthy” SNP alleles. In parallel with increasing insights into the non-coding genome, emerging studies reveal that most disease-associated SNPs reside within a non-coding sequence, including lncRNA genes. These developments lay the foundation for deciphering the aetiology of complex diseases, including type 2 diabetes (T2D), and its association with an increased risk of certain cancers. Here, deploying a customized annotation pipeline on GWAS datasets, we successfully identified, and characterized, six genetic variants significantly associated with both T2D and cancer in lncRNA or genes and other non-coding regions. These variants suggest evidential proof of a shared genetic architecture between the two diseases, help to functionally explain the casual association of diabetes with cancer, and comprise a potential shortlist of candidate drug targets. ABSTRACT: Numerous epidemiological studies place patients with T2D at a higher risk for cancer. Many risk factors, such as obesity, ageing, poor diet and low physical activity, are shared between T2D and cancer; however, the biological mechanisms linking the two diseases remain largely unknown. The advent of genome wide association studies (GWAS) revealed large numbers of genetic variants associated with both T2D and cancer. Most significant disease-associated variants reside in non-coding regions of the genome. Several studies show that single nucleotide polymorphisms (SNPs) at or near long non-coding RNA (lncRNA) genes may impact the susceptibility to T2D and cancer. Therefore, the identification of genetic variants predisposing individuals to both T2D and cancer may help explain the increased risk of cancer in T2D patients. We aim to investigate whether lncRNA genetic variants with significant diabetes and cancer associations overlap in the UAE population. We first performed an annotation-based analysis of UAE T2D GWAS, confirming the high prevalence of variants at or near non-coding RNA genes. We then explored whether these T2D SNPs in lncRNAs were relevant to cancer. We highlighted six non-coding genetic variants, jointly reaching statistical significance in T2D and cancer, implicating a shared genetic architecture between the two diseases in the UAE population.