rs10750397 (ETS1 / LINC02098): Type 2 Diabetes Locus

Key takeaways

• rs10750397 sits between LINC02098 (a long non-coding RNA gene) and ETS1 (a transcription factor gene) and has been flagged as a candidate type 2 diabetes susceptibility locus in large-scale genetic studies.
• It was identified as part of 286 previously unreported T2D risk loci in a multi-ethnic meta-analysis covering more than 1.4 million participants.
• Effect sizes at newly discovered T2D loci like this one are modest, averaging about 0.032 per allele on a log-odds scale.
• A cross-trait genetic study found that long non-coding RNA genes expressed in the pituitary gland may contribute to shared genetic risk between type 2 diabetes and schizophrenia, a finding relevant to the LINC02098 gene class.
• Evidence for this locus is at the discovery stage; independent replication specific to rs10750397 is not documented in the provided studies.

What the research says A multi-ethnic GWAS meta-analysis of 228,499 T2D cases and 1,178,783 controls identified 286 previously unreported autosomal T2D loci, with novel loci showing an average effect size of approximately 0.032 per allele on a log-odds scale, and genome-wide chip heritability explaining 19% of T2D risk on a liability scale PMID 32541925. A European-ancestry fine-mapping analysis of 74,124 cases and 824,006 controls, using high-density imputation across approximately 27 million variants, identified 135 novel T2D loci and improved causal-variant resolution through integration of islet regulatory annotations to a median credible set size of 32 variants per signal PMID 31533269. A cross-trait genetic analysis found a weak but statistically significant negative genome-wide genetic correlation between T2D and schizophrenia (rg = -0.098, p = 0.009 in Europeans) across a combined sample of 1,466,906 subjects, identifying 25 independent pleiotropic variants with associated genes enriched for expression in the pituitary gland (p = 1.9E-6) and including long non-coding RNA class genes PMID 36042533.

Reported associations

• Type 2 diabetes (multi-ethnic discovery): The LINC02098 - ETS1 genomic region was identified among 286 newly reported T2D susceptibility loci in a meta-analysis of 228,499 cases and 1,178,783 controls spanning European, African American, Hispanic, South Asian, and East Asian ancestry groups; novel-locus average effect size was approximately beta 0.032 per allele PMID 32541925
• Type 2 diabetes (European fine-mapping): The region also falls within the broader set of 135 novel T2D loci identified through high-density imputation in 74,124 cases and 824,006 European-ancestry controls, where causal variant localisation was refined using islet-specific epigenome maps PMID 31533269
• Cross-trait signal - type 2 diabetes and schizophrenia: LINC02098 belongs to the long non-coding RNA gene class highlighted in a cross-trait analysis as candidate effectors shared between T2D and schizophrenia; pituitary-expressed lncRNA genes were specifically enriched (p = 1.9E-6) among the 61 genes identified at effective pituitary loci, and 25 independent variants were reported as jointly associated with both conditions PMID 36042533

Evidence quality The primary T2D association evidence comes from two large studies. Vujkovic et al. (228,499 cases, 1,178,783 controls) reported genome-wide significant associations (p < 5x10-8) for 286 novel autosomal loci, and Mahajan et al. (74,124 cases, 824,006 controls) identified 135 novel loci with fine-mapping credible sets refined to a median of 32 variants per signal PMID 32541925 PMID 31533269. Both studies reported genome-wide chip heritability of approximately 18-19% for T2D on a liability scale. The cross-trait signal reported by Cai et al. is based on a weak genetic correlation (rg = -0.098) that remained significant in Europeans only after Bonferroni correction, and the 25 identified pleiotropic variants are at the gene-class enrichment level rather than having been traced to single-variant resolution PMID 36042533. No variant-specific fine-mapping, functional data, or independent replication for rs10750397 as a distinct signal is reported in the provided studies. The lncRNA LINC02098 is a plausible candidate effector based on gene-class enrichment in pituitary tissue, but a direct causal role has not been established. Overall, evidence is preliminary and discovery-level.

Lifestyle considerations No lifestyle considerations on file for this variant.