Polymorphic Inversions Underlie the Shared Genetic Susceptibility of Obesity-Related Diseases

Abstract

The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.

Keywords: asthma; common diseases; diabetes; disease co-occurrence; genetic inversions; genomic variation; human traits; hypertension; obesity; obesity-related diseases.

Figure 1

Discovery and Validation Datasets The flow chart shows the discovery sample and the validation datasets as well as the datasets used for post-genomic data analyses. Sample size (n) used from each dataset after performing quality control are also shown.

Figure 2

Association Analyses between 21 Inversions and 8 Diseases (in Bold) and 17 Traits and the Co-occurrence of Obesity with 6 Other Complex Diseases Circles represent the direction (color) and the two-tailed -log10 p value (size) of the association for different groups of traits (morphometric, metabolic, lipidic, respiratory, and behavioral) and the epidemiological well-established co-occurrence of obesity-related diseases. Inversions are grouped by size and features: (1) submicroscopic are large (0.4–4 Mb) encompassing multiple genes and flanked by segmental duplications; (2) intragenic are located within a gene, either intronic or containing one exon; and (3) intergenic are enriched in pleitropic regions.

Figure 3

Validation of Positive Associations between the Inversion 8p23.1 with Diabetes, Obesity, and Their Co-occurrence in the 70KT2D Dataset and Transcriptional Allelic Effects in Samples from EGCUT Biobank and GTEx Tissues (A–C) 95% confidence intervals and meta-analysis of datasets belonging to 70KT2D for the association of inversion 8p23.1 with diabetes (A), obesity (B), and obese and diabetic individuals (C). (D) Differential expressed genes at inversion genotypes (at 5% FDR) in different tissues from GTEx, showing effect of the I allele (color) and the two-tailed -log10 p value (size) of the association. (E) Differentially expressed genes at inversion genotypes (at 5% FDR) in blood samples from EGCUT Biobank. (F) FAM66A gene expression interaction between diabetic status and inversion 8p23.1 in pancreatic islets samples (p = 0.0254). The boxplots indicate the interquantile range and median of gene expression levels.

Figure 4

Mechanisms Underlying the Inversion Association with Diabetes (A) Islet-specific expression of inversion 8p23.1 genes. We observed a cluster of islet-specific genes, mainly lncRNAs, next to the distal inversion breakpoint that could be separated from regulatory elements located inside the inverted region. The bottom panel depicts an eQTLs (rs1478898) of FAM66A disrupted by the inversion distal breakpoint.FAM66D has its gene body split in two by the inversion, and would also have its promoter separated from its eQLT SNP (rs140730217) by the inversion. This could be the most likely causal candidate. (B) Same information for the inversion 16p11.2. TUFM and EIF3C have their lead eQTL SNP separated by the inversion breakpoint. There is no evidence in the centiSNP database for SNP rs42861 to be causal, suggesting that it should be in LD with the causal variant. This promoter region SNP is located in a segmental duplication block that is closer to TUFM in the inverted haplotypes. Therefore, positional changes made by the inversion can affect TUFM expression by separating the gene from regulatory sequences and subsequently increasing obesity risk.

Figure 5

Mediation Effect of Obesity in the Causal Link between Inversions and Diabetes and Hypertension (A) Mediation analysis of obesity in the association between inversion 8p23.1 and diabetes, showing a proportion of the mediation of 38% (p value < 10e−6), which is the Best Bayesian Network when analyzing these three variables. Significant test for the proportion of the median showed a p value < 10⁻¹⁶. (B) Best Bayesian Network based on AIC obtained after including obesity, hypertension, diabetes, and inversions 8p23.1, 16p11.2, and 11q13.2. Results are obtained from UKB data.