Identification Of Novel Variants For Type 2 Diabetes And Early Body Mass Index Using Genome-wide Bivariate Analysis

[Background and Objective]Diabetes is a group of systemically metabolic disorders which is characterized by long-term hyperglycemia due to scarcity of insulin secretion,deficiency of insulin action,or both.It has become a seriously public health problem worldwide.To date,more than 400 million people throughout the world are suffering from diabetes.Over 90%of cases have type 2 diabetes(T2D).Diabetes has become one of leading causes of death,disability,and increased healthcare costs.Clinical and epidemiological findings implicate an association between type 2 diabetes(T2D)and birth weight(BW)/childhood body mass index(CBMI).Numerous studies have demonstrated that low BW and high CBMI can lead to increased risk of developing T2D in later life.Genome-wide association studies(GWASs)have successfullyrevealed a number of single nucleotide polymorphisms(SNPs)for T2D which were also reported inBW/CBMItrait.Despite these potential genetic variationsfound to be reproducedly associated with both T2D and BW/CBMI,these SNPs only explain a small proportion of heritability.Recent studies reported the pleiotropy-informed conditional false discovery rate(PCFDR)method,which requires only summary statistics from GWAS,could provide increased power to detect SNPs in GWAS results and elucidate mechanistic relationships between genetically related phenotypes.In the present study we applied the PCFDR method to identify additional and novel genetic loci of these three traits and to determine whether T2D shares susceptibility loci with BW/CBMI,with the aim of gaining insights into the common intervention target between T2D and BW/CBMI.[Methods]The study applied the PCFDRmethod to integrate the current largest GWAS summary data of T2D and BW/CBMI in the whole globe for bivariate analysiswith a significance threshold of conditional false discovery rate(cFDR)<0.05.[Results]Pleiotropic enrichment of T2D SNPs conditioned on association with BW/CBMIConditional Q-Q plot is a common method to graphically assess the pleiotropic enrichment of genetic loci.By jointly analyzing independent multi-center GWASsummary statistics of T2Dand BW/CBMI,we founda strong enrichment of genetic variants in T2D conditioned on different levels of association with BW/CBMI assessed by conditional Q-Q plots.Loci identified with cFDRTo identify specific loci associated with T2D and BW/CBMI,we computed cFDR,an extension of the standard FDR framework,which incorporates information from GW AS summary statistics of the conditional phenotype to demonstrate the probability that a SNP is not associated with principal phenotype given its p-values for the principal and conditional phenotypes are below the indicated cut-offs.Conditioned on BW and CBMI separately,the study identified 133 and 139 loci including 120 and 125 novel ones associated with T2D(cFDR<0.05).13 significant BW-associated SNPs(12 novel ones)and 37 significant BW-associated loci(25 novel ones)conditioned on T2D(cFDR<0.05)were identified.To determine pleiotropic loci,the conjunctional cFDR(ccFDR)was calculated,which refers to the possibility that a given SNP has a false positive association with both the principal and conditional traits.The ccFDR was computed as the maximum cFDR values(i.e.T2D|BW and BW|T2D)of the two traits.9pleiotropic loci including 7 novelones were shared with BW(conjunction cFDR<0.05)and 10 new pleiotropic SNPs were shared with CBMI(conjunction cFDR<0.05).2 novel SNPs located at the CDKAL1(rs1012635,cFDR=1.91E-02)and ADCY5(rs4677887,cFDR=1.67E-02)genes are noteworthy.These two genes increase the risk of T2D and low BW through the pathway of the "fetal insulin hypothesis".GeneGNPDA2may be the link between T2D and CBMI because it influence the risk of T2D and childhood obesity through processes in controlling weight of the central nervous system.Network and pathway analysisTo explore the functional association among identified T2D target genes and networks involved in the biological function of T2D,the 133 significant SNPs conditioned on BW corresponding genes were uploaded into the STRING 10.0 database.Interestingly,the network consisted of positive regulation of cellular process genes and negative regulation of transcription from RNA polymerase II promoter genes,showing a strong protein-protein interaction among proteins corresponding tothe T2D target genes.In addition,we applied the network analysis to the 139 significant T2D-associated SNPs conditioned on BW corresponding genes and the network consisted of genes that play an important role in multicellular organismal development,anatomical structure development and positive regulation of cellular component organization.These resultsrevealed strong association between the topological properties and biological function of T2D target genesTo systematically investigate whether the observed pleiotropic SNPs were T2D and BW/CBMI specific,GO analysis was conducted,revealing a variety of biological processes,(e.g.adenosine receptor signaling pathway[P = 4.29 × 10-6],G-protein-coupled purinergic receptor signaling pathway[P = 4.29 × 10-6]and adenylate cyclase-activating dopamine receptor signaling pathway[P = 9.79 × 10-6])that are closely related to T2D and birth weight.[Conclusion]The present study demonstrated high efficiency of the cFDR method in improving the identification of novel genetic variants of both T2D and BW/CBMI.The findings offer novel insights into potential shared genetic mechanisms in T2D and BW/CBMI,which may form a basis for further biological experiments and clinical replication.Several pleiotropic loci were identified between T2D and BW/CBMI by leveraging GWAS results.The results make it possible to explain a greater proportion of trait heritability and improve our understanding of the shared pathophysiology between T2D and BW/CBMI.