Insights from rare variants into the genetic architecture and biology of youth-onset type 2 diabetes

Abstract

Youth-onset type 2 diabetes (T2D) is a growing public health concern. Its genetic basis and relationship to other forms of diabetes are largely unknown. To gain insight into the genetic architecture and biology of youth-onset T2D, we analyzed exome sequences of 3,005 youth-onset T2D cases and 9,777 ancestry matched adult controls. We identified (a) monogenic diabetes variants in 2.1% of individuals; (b) two exome-wide significant (P < 4.3×10^-7) common coding variant associations (in WFS1 and SLC30A8); (c) three exome-wide significant (P < 2.5×10^-6) rare variant gene-level associations (HNF1A, MC4R, ATX2NL); and (d) rare variant association enrichments within 25 gene sets broadly related to obesity, monogenic diabetes, and β-cell function. Many association signals were shared between youth-onset and adult-onset T2D but had larger effects for youth-onset T2D risk (1.18-fold increase for common variants and 2.86-fold increase for rare variants). Both common and rare variant associations contributed more to youth-onset T2D liability variance than they did to adult-onset T2D, but the relative increase was larger for rare variant associations (5.0-fold) than for common variant associations (3.4-fold). Youth-onset T2D cases showed phenotypic differences depending on whether their genetic risk was driven by common variants (primarily related to insulin resistance) or rare variants (primarily related to β-cell dysfunction). These data paint a picture of youth-onset T2D as a disease genetically similar to both monogenic diabetes and adult-onset T2D, in which genetic heterogeneity might be used to sub-classify patients for different treatment strategies.

Figure 1. Scheme of the study and genetic discovery.

a. Whole-exome sequence data of youth-onset T2D cases were matched to that of external non-diabetic controls using genetic PCs and a SVD based method resulting in 3,005 cases and 9,777 controls for single variant and gene-level association analysis. b. Single variant association analysis revealed four variants passing exome wide significance (P < 4.3 × 10^{− 7}). c. Gene-level association analysis showed three genes associated with youth-onset T2D at exome-wide significance (P < 2.6 × 10⁻⁶). Blue dots represent previously known variants or genes of T2D. GATK, genome analysis tool kit; OR, odds ratio; PC, principal componants; SVD, singular value decomposition; WES, whole-exome sequencing.

Figure 2. Pathways involved in obesity and β-cell function are enriched in youth-onset T2D.

a. Gene set enrichment analysis using hypergeometric test with top 50 gene-level association signals in youth-onset T2D identified 25 Human Phenotype Ontology gene sets which had significant overlap and were related to metabolic phenotypes of diabetes. These 25 gene sets were categorized into three subgroups of ‘obesity’, ‘β-cell function’, and ‘others’. b. Wilcoxon rank-sum test using these 25 gene sets revealed representative sets with significant association enrichments beyond the top 50 associated genes, such as ‘HP_OVERWEIGHT’, ‘HP_TRANSIENT_NEONATAL_DIABETES_MELLITUS’, and ‘HP_ELEVATED_HEMOGLOBIN_A1C’. c. Gene set clusters of ‘obesity’ and ‘β-cell function’ showed significant enrichment (P < 0.05) when combining genes across all sets in the cluster. Background denotes matched genes with similar numbers and frequencies of variants within them.

Figure 3. Genetic architecture and liability variance explained by common and rare variants.

a. Liability variance explained by common variants and gene-level associations in youth-onset T2D and adult-onset T2D for exome-wide significant associations (EWS), 10 Tier 3 genes and same number of common variants (Tier 3), top 25 significant gene-level and common variant associations (Top 25), and 46 Tier 4 genes and same number of common variants (Tier 4). The liability variance explained by common variants increased by 3.5 – 4.2-fold in youth-onset T2D compared to adult-onset T2D. There was even larger 5.0 – 9.0-fold increase in liability variance explained by rare variant gene-level associations in youth-onset T2D. b. Odds ratio and allele frequency distribution of Tier 3 gene-level and common variant association signals and their liability variance explained in youth-onset T2D and adult-onset T2D.

Figure 4. Individual genetic risk confered by common and rare variants.

a. Fraction of individuals having high genetic risk confered by MODY variants, rare variant score, common variant score, or combined variant score. Among 3,005 youth-onset T2D cases, 2.1% carried MODY variants, 3.2% had high rare variant score with OR ≥ 5, 5.9% had high common variant score with OR ≥ 5, and 0.2% had high combined score with OR ≥ 5. b. For the 612 individuals having high combined variant score with OR ≥ 3, the contribution of rare variant score was higher at the higher end of the combined variant score. c. MODY cases had earlier age of diagnosis, lower BMI Z-score, and lower log₁₀(C-peptide) level. d. Rare variant score was associated with earlier age at diagnosis and common variant score was associated with higher log₁₀(C-peptide) level even after excluding MODY cases.