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. 2017 Oct;9(10):898-907.
doi: 10.1111/1753-0407.12510. Epub 2017 Jan 20.

Increased identification of novel variants in type 2 diabetes, birth weight and their pleiotropic loci

Chun-Ping Zeng  1   2 , Yuan-Cheng Chen  1 , Xu Lin  1 , Jonathan Greenbaum  3 , You-Ping Chen  2 , Cheng Peng  1 , Xia-Fang Wang  1 , Rou Zhou  1 , Wei-Min Deng  4 , Jie Shen  1 , Hong-Wen Deng  1   3
Affiliations

Increased identification of novel variants in type 2 diabetes, birth weight and their pleiotropic loci

Chun-Ping Zeng et al. J Diabetes. 2017 Oct.

Abstract

Background: Clinical and epidemiological findings point to an association between type 2 diabetes (T2D) and low birth weight. However, the nature of the relationship is largely unknown. The aim of this study was to identify novel single nucleotide polymorphisms (SNPs) in T2D and birth weight, and their pleiotropic loci.

Methods: A pleiotropy-informed conditional false discovery rate (cFDR) method was applied to two independent genome-wide association studies (GWAS) summary statistics of T2D (n = 149 821) and birth weight (n = 26 836).

Results: A conditional Q-Q plot showed strong enrichment of genetic variants in T2D conditioned on different levels of association with birth weight. 133 T2D-associated SNPs, including 120 novel SNPs, were identified with a significance threshold of cFDR < 0.05; 13 significant birth weight-associated SNPs, including 12 novel SNPs (cFDR < 0.05) were identified. Conjunctional cFDR (ccFDR) analysis identified nine pleiotropic loci, including seven novel loci, shared by both T2D and birth weight (ccFDR < 0.05). Two novel SNPs located at the CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1; rs1012635; cFDR < 0.05) and adenylate cyclase 5 (ADCY5; rs4677887; cFDR < 0.05) genes are of note. These two genes increase the risk of T2D and low birth weight through the pathway of the "fetal insulin hypothesis."

Conclusion: Several pleiotropic loci were identified between T2D and birth weight 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 birth weight.

Keywords: 2型糖尿病; birth weight; genome-wide association study; pleiotropy; type 2 diabetes; 全基因组联分析; 出生体重; 基因多效性.

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Conflict of interest statement

Disclosure

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Conditional Q–Q plot. Stratified Q-Q plot of enrichment versus nominal −log10 P-values (corrected for inflation) in (a) type 2 diabetes (T2D) as a function of significance of the association with birth weight (T2D|birth weight) and (b) birth weight as a function of significance of the association with T2D (birth weight|T2D) below the standard genome-wide association study threshold of P < 5 × 10−8 at the level of −log10(P) > 0, −log10(P) > 1, −log10(P) > 2, and −log10(P) > 3 corresponding to P < 1, P < 0.1, P < 0.01, and P < 0.001, respectively. Dashed lines indicate the null-hypothesis.
Figure 2
Figure 2
Functional protein association network analysis for type 2 diabetes (T2D) susceptibility genes. Connections are based on coexpression and experimental evidence with a STRING 10.0 (http://string-db.org/, accessed 1 May 2016) summary score above 0.4. The network that related to positive regulation of cellular process and negative regulation of transcription from RNA polymerase II promoter showed significant enrichment for T2D susceptibility genes. Each filled node denotes a gene; edges between nodes indicate protein–protein interactions between protein products of the corresponding genes. Different edge colors represent the types of evidence for the association. Definitions for all protein symbols are given in Table S2.
Figure 3
Figure 3
“Conjunctional Manhattan plot” of conjunctional −log10 (conditional false discovery rate [cFDR]) values for type 2 diabetes (T2D) and birth weight. Single nucleotide polymorphisms with conjunctional −log10 cFDR >1.3 (i.e. cFDR < 0.05) are shown above the red line. The figure marks the chromosomal locations of significant loci. Details for all significant loci are given in Table 2.
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