Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
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We are grateful for the OP9-K cells kindly shared by the laboratory of A. Kopin (Tufts Medical Center). The authors gratefully acknowledge the help of the MRC Epidemiology Unit Support Teams, including the Field Teams, the Laboratory Team and the Data Management Team, and of the staff of the Wellcome Trust Clinical Research Facility.
This study was funded by the UK Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). Funding for the InterAct project was provided by the EU FP6 program (grant LSHM_CT_2006_037197). This work was funded, in part, through an EFSD Rising Star award to R.A.S. supported by Novo Nordisk. D.B.S. is supported by Wellcome Trust grant 107064. M.I.M. is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. M.v.d.B. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. I.B. is supported by Wellcome Trust grant WT098051. S.O'R. acknowledges funding from the Wellcome Trust (Wellcome Trust Senior Investigator Award 095515/Z/11/Z and Wellcome Trust Strategic Award 100574/Z/12/Z).
Concept and design: L.A.L., I.B., N.J.W., D.B.S., C.L., S.O'R. and R.A.S. Generation, acquisition, analysis and/or interpretation of data: all authors. Drafting of the manuscript: L.A.L., I.B., N.J.W., D.B.S., C.L., S.O'R. and R.A.S. Critical review of the manuscript for important intellectual content and approval of the final version of the manuscript: all authors.
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 2 Design of the study, investigated phenotypes, sources of data and sample size.
The reported sample size is the maximum available for a given trait or set of traits in this study. *In the study by Knowles and colleagues (PubMed ID: 25798622), insulin sensitivity was measured by euglycemic clamp or insulin suppression test in 2,764 European individuals from four cohorts. IR, insulin resistance; FIadjBMI, fasting insulin levels adjusted for body mass index; TG, triglyceride levels; HDL, high-density lipoprotein cholesterol levels; ISI, insulin sensitivity index; DEXA, dual-energy X-ray absorptiometry; BF%, body fat percentage; FPLD1, familial partial lipodystrophy type 1; MAGIC, Meta-Analyses of Glucose- and Insulin-related traits Consortium; GLGC, Global Lipids Genetics Consortium; GIANT, Genetic Investigation of ANthropometric Traits; DIAGRAM, DIAbetes Genetics Replication And Meta-analysis; CARDIOGRAM, Coronary ARtery DIsease Genome-wide Replication and Meta-analysis; C4D, Coronary Artery Disease Genetics consortium.
Supplementary Figure 3 Combined directional Manhattan plots of the association with insulin-resistance-related phenotypes.
(a–c) Manhattan plots of the association of SNPs with fasting insulin adjusted for body mass index (FIadjBMI) (a), triglycerides (b) and HDL cholesterol (c). We plotted only variants with FIadjBMI, triglycerides and HDL cholesterol (P < 0.005 for each phenotype). All associations are represented for the FIadjBMI-raising allele. The 630 alleles associated with higher FIadjBMI, higher triglycerides and lower HDL cholesterol are plotted in dark red. The graph also plots 21 variants that met the P-value threshold for the three phenotypes but were not associated in the required direction (gray). For graphic display purposes, P values below 10−20 are represented as 10−20.
Numbers refer to SNPs. FIadjBMI, fasting insulin adjusted for body mass index; HDL, high-density lipoprotein cholesterol; TG, triglycerides.
The figure reports associations of the genetic scores comprising the 53 or 43 SNPs with fasting insulin adjusted for body mass index, triglycerides and HDL cholesterol in up to 6,101 participants of the Fenland study who were not included in any of the discovery efforts used for identification of the 53 loci. Squares indicate the central estimate of the β coefficient; error bars represent 95% confidence intervals. N, number of participants; FIadjBMI, fasting insulin adjusted for body mass index; HDL, high-density lipoprotein; SD, standard deviation.
Supplementary Figure 6 Associations with glycemic and anthropometric traits and with disease endpoints at the 53 genomic loci.
The heat map represents z scores for the association of the lead insulin-raising allele at each locus. Loci are ranked on the basis of their z scores for fasting insulin (largest to smallest). With the exception of fasting insulin, none of the association analyses were adjusted for body mass index. N, maximum sample size; FIadjBMI, fasting insulin adjusted for body mass index; HDL, high-density lipoprotein cholesterol; BMI, body mass index; WHR, waist–hip ratio; CHD, coronary heart disease; T2D, type 2 diabetes. Color scale: red indicates positive associations for the insulin-raising allele at each locus, while blue indicates negative associations. Asterisks indicate known loci for the traits, i.e., those for which our lead SNP is within 500 kb on either side of a lead SNP from the largest GWAS for that trait.
Supplementary Figure 7 Associations of the genetic scores comprising the 53 or 43 SNPs with glycemic and anthropometric traits in large-scale meta-analyses and in the Fenland study.
(a) Association of the genetic scores with anthropometric and glycemic traits in meta-analyses of genetic association studies. Body mass index, waist–hip ratio, and waist and hip circumference data are from the GIANT consortium and the UK Biobank study. Body fat percentage data are from the UK Biobank, EPIC-Norfolk and Fenland studies. Fasting plasma glucose, 2-h glucose and HbA1c data are from the MAGIC consortium. Leg fat mass data are from the EPIC-Norfolk and Fenland studies. Squares with error bars represent the per-allele β coefficients in standard deviation units and their 95% confidence intervals. (b) Association with the same traits in participants of the Fenland study not included in the discovery efforts that contributed to the identification of the 53 loci. Because HbA1c has been measured only in a subset of Fenland participants, the HbA1c analysis also includes individuals from the InterAct study subcohort who did not take part in the discovery efforts that contributed to the identification of the 53 loci. Squares with error bars represent the per-allele β coefficients in standard deviation units and their 95% confidence intervals. Red and blue squares represent the results of the 53-SNP and 43-SNP genetic scores, respectively. None of the results presented in the figure were adjusted for body mass index. N, number of participants; SD, standard deviation; BMI, body mass index; WHR, waist–hip ratio; FPG, fasting plasma glucose.
Supplementary Figure 8 Associations of the 53-SNP genetic score with detailed anthropometric variables from dual-energy X-ray absorptiometry.
The figure represents the association of quintiles of the 53-SNP genetic score with the absolute values of compartmental and total fat mass. Data are from 9,747 participants of the Fenland study. The Fenland population was divided into quintiles of the distribution of the genetic score, and each quintile was compared with the bottom (reference category). Squares with error bars represent the β coefficients in grams for individuals in the exposure category as compared with the reference category and their 95% confidence intervals.
Supplementary Figure 9 Associations of the rs4976033[G] allele near PIK3R1 with continuous metabolic traits and cardiometabolic disease endpoints.
(a) Associations with continuous traits. (b) Associations with disease endpoints. Squares with error bars represent the β coefficients (a) or odds ratios (b) and their 95% confidence intervals. HDL, high-density lipoprotein; LDL, low-density lipoprotein; BMI, body mass index; WHR, waist–hip ratio; FIadjBMI, fasting insulin adjusted for BMI; FPG, fasting plasma glucose; 2hr glucose, glucose at 2 h during an oral glucose challenge; SD, standard deviation; OR, odds ratio.
Supplementary Figure 10 Associations of functional variants in LPL with cardiometabolic traits and disease endpoints.
(a) Association of the gain-of-function p.Ser447* (rs328; left) and the loss-of-function p.Asp36Asn (rs1801177; right) variants in LPL with lipid levels, anthropometric traits, liver markers and glycemic traits. (b) Association of the two variants with the risk of coronary heart disease (from the Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators; PubMed ID: 26934567) and that of type 2 diabetes. Squares with error bars represent the β coefficients (a) or odds ratios (b) and their 95% confidence intervals. HDL, high-density lipoprotein; LDL, low-density lipoprotein; BMI, body mass index; WHR, waist–hip ratio; VAT, visceral adipose tissue; ALT, alanine aminotransferase; GGT, γ-glutamyltransferase; FIadjBMI, fasting insulin adjusted for BMI; FPG, fasting plasma glucose; 2hr, glucose at 2 h during an oral glucose challenge; SD, standard deviation; OR, odds ratio.
Supplementary Figure 11 Mechanistic hypothesis for the implication of putative effector genes in the observed associations and selection of genes for experimental validation in cellular models of adipogenesis.
(a) Mechanistic hypothesis. (b) Selection criteria to prioritize genes for experimental validation. (c) Selection flowchart. Numbers in c refer to loci meeting certain selection criteria. *We did not take forward the KLF14 gene to experimental validation because previous studies on the role of this gene in metabolic disease suggest complex etiological mechanisms at this locus, including a possible parent-of-origin effect.
Supplementary Figure 12 Associations with fasting insulin adjusted for body mass index, body mass index or fasting insulin of the 53 polymorphisms identified in this study.
(a) Association of the 53 lead polymorphisms from our study with FIadjBMI as a function of the association with BMI. There was no clear bias in the association with FIadjBMI (linear regression between the β coefficients of the 53 polymorphisms, P = 0.26). (b) Association with FI (unadjusted for BMI) of the lead 53 polymorphisms as a function of the association with FIadjBMI. The line of fit was aligned with the line of equality consistent with no bias. In a, the dark red line and surrounding areas represent the line of fit with 95% confidence areas. The dashed gray line in b represents the line of equality. Data on fasting insulin associations are from the MAGIC consortium; data on BMI associations are from the GIANT consortium.
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Lotta, L., Gulati, P., Day, F. et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet 49, 17–26 (2017). https://doi.org/10.1038/ng.3714
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