rs1108842 (GNL3): Adiponectin and Brain Expression

Key takeaways

• rs1108842 reduces GNL3 expression in brain cerebellar regions, based on tissue data from 953 donors.
• Cross-ancestry genome-wide studies link the GNL3 locus to circulating adiponectin, a fat-cell hormone inversely associated with type 2 diabetes and insulin resistance.
• A combined genome-wide study of 248,482 participants placed this region among 187 loci for general cognitive function.
• Adiponectin-lowering variants at this and related loci collectively associate with higher triglycerides, lower HDL-cholesterol, and increased type 2 diabetes risk in consortium data.
• The variant also affects expression of PBRM1 and NEK4 in thyroid, and ITIH4 in arterial tissue.

What the research says A 2024 cross-ancestry genome-wide association study (GWAS) meta-analysis in up to 46,434 individuals identified 22 loci associated with adiponectin levels and applied statistical fine-mapping using FINEMAP and SuSiE - tools that narrow a broad GWAS signal down to its most probable causal variants - identifying 45 causal variants with posterior probability above 0.9, while a proposed Gene Priority Score (GPScore) ranked 30 probable target genes centered on insulin and adiponectin signaling pathways. An earlier 2012 multi-ethnic GWAS meta-analysis in 45,891 individuals confirmed adiponectin-associated loci and showed that a multi-SNP genotypic risk score spanning these loci was associated with increased type 2 diabetes risk (p = 4.3x10-3, n = 22,044), elevated triglycerides (p = 2.6x10-14, n = 93,440), increased waist-to-hip ratio (p = 1.8x10-5, n = 77,167), and lower HDL-cholesterol (p = 4.5x10-13, n = 96,748). A 2020 multi-trait analysis of GWAS data (MTAG) - a method that boosts statistical power by combining genetically correlated traits - leveraging education and intelligence (genetic correlation rg = 0.70 between the two) in an effective 248,482 participants identified 187 independent loci for general cognitive function implicating 538 genes, with neurogenesis and myelination highlighted as relevant biological pathways.

Reported associations

• Adiponectin levels: Identified as an associated locus in a 2024 cross-ancestry GWAS meta-analysis (n up to 46,434) discovering 22 genome-wide significant adiponectin loci including 7 previously unreported ones, with 45 causal variants fine-mapped at high confidence.
• Adiponectin levels (independent replication): Confirmed in a 2012 multi-ethnic GWAS meta-analysis (n = 45,891) identifying 10 novel loci and demonstrating expression of 18 candidate genes in 436 human adipocyte samples (p<3x10-4 after multiple testing correction).
• General cognitive function: Included among 187 genome-wide significant loci in a combined GWAS of education and intelligence (effective n = 248,482) implicating 538 genes in pathways including neurogenesis and myelination.
• Type 2 diabetes risk (multi-SNP aggregate): A genotypic risk score aggregating all adiponectin-associated loci was linked to increased T2D risk (p = 4.3x10-3, n = 22,044); this is a collective effect across many variants, not attributable to this variant alone.
• Metabolic syndrome traits (multi-SNP aggregate): The same aggregate score associated with elevated triglycerides (p = 2.6x10-14, n = 93,440), increased waist-to-hip ratio (p = 1.8x10-5, n = 77,167), reduced HDL-cholesterol (p = 4.5x10-13, n = 96,748), elevated 2-hour post-load glucose (p = 4.4x10-3, n = 15,234), and increased fasting insulin (p = 0.015, n = 48,238).

Evidence quality The adiponectin evidence draws from two independent large GWAS meta-analyses of 45,891 and 46,434 participants, both achieving genome-wide significance (p < 5x10-8). The 2024 study strengthened causal inference through cross-ancestry fine-mapping, identifying 45 variants with posterior probability above 0.9 for causality. For cognitive function, the MTAG approach leverages the genetic correlation (rg = 0.70) between intelligence and educational attainment to boost statistical power; the 187 resulting loci replicated the pattern of genetic correlations seen in prior intelligence GWASs, supporting validity. A key limitation is that MTAG-derived loci may partly reflect educational attainment pathways rather than core cognitive ability. No individual odds ratio or beta coefficient for rs1108842 alone is reported in the provided evidence; the metabolic trait effect sizes cited are for multi-SNP aggregate scores across all adiponectin loci. Adiponectin heritability estimated from twin and family studies ranges from 30 to 70 percent, consistent with a complex polygenic architecture.

Tissue-specific expression effects

• GNL3: Reduced expression in both brain cerebellum and cerebellar hemisphere, the gene from which this variant draws its locus name. GTEx Portal
• PBRM1: Increased expression in thyroid tissue. GTEx Portal
• NEK4: Reduced expression in thyroid tissue. GTEx Portal
• ITIH4: Increased expression in aortic and tibial arterial tissue. GTEx Portal
• NT5DC2: Reduced expression in EBV-transformed lymphocytes. GTEx Portal
• ENSG00000275956: Reduced expression in brain cerebellum; no standard gene symbol is assigned in the provided data. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.