Heritability and genome-wide association analyses of fasting plasma glucose in Chinese adult twins

• Published in: BMC genomics Vol. 21; no. 1; pp. 491 - 11
• Main Authors: Wang, Weijing, Zhang, Caixia, Liu, Hui, Xu, Chunsheng, Duan, Haiping, Tian, Xiaocao, Zhang, Dongfeng
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18-07-2020; BioMed Central; BMC
• Subjects: Adrenergic receptors; Alanine; Asian Continental Ancestry Group - genetics; Biomarkers; Blood glucose; Blood Glucose - genetics; China; Chinese; Chromosomes; Diabetes; Diabetes mellitus; Diagnostic systems; Fasting; Fasting plasma glucose; Gene expression; Gene loci; Genes; Genetic aspects; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Glucagon; Glucose; Growth factors; Heritability; Homeostasis; Humans; Inheritance Patterns; Insulin; Interleukin 1; Interleukin 1 receptors; Laboratory testing; Levels; Mathematical models; Metabolism; Methionine; Middle Aged; Morbidity; Multivariate statistical analysis; Parameters; Physiological aspects; Polymorphism, Single Nucleotide; Population; Population genetics; Potassium channels; Protein expression; Proteins; Signal transduction; Signaling; Single-nucleotide polymorphism; Therapeutic applications; Twins; China; Chinese; Heritability; Fasting plasma glucose; Genome-wide association study; Twins
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-020-06898-z

Currently, diabetes has become one of the leading causes of death worldwide. Fasting plasma glucose (FPG) levels that are higher than optimal, even if below the diagnostic threshold of diabetes, can also lead to increased morbidity and mortality. Here we intend to study the magnitude of the genetic influence on FPG variation by conducting structural equation modelling analysis and to further identify specific genetic variants potentially related to FPG levels by performing a genome-wide association study (GWAS) in Chinese twins.
The final sample included 382 twin pairs: 139 dizygotic (DZ) pairs and 243 monozygotic (MZ) pairs. The DZ twin correlation for the FPG level (r
 = 0.20, 95% CI: 0.04-0.36) was much lower than half that of the MZ twin correlation (r
 = 0.68, 95% CI: 0.62-0.74). For the variation in FPG level, the AE model was the better fitting model, with additive genetic parameters (A) accounting for 67.66% (95% CI: 60.50-73.62%) and unique environmental or residual parameters (E) accounting for 32.34% (95% CI: 26.38-39.55%), respectively. In the GWAS, although no genetic variants reached the genome-wide significance level (P < 5 × 10
), 28 SNPs exceeded the level of a suggestive association (P < 1 × 10
). One promising genetic region (2q33.1) around rs10931893 (P = 1.53 × 10
) was found. After imputing untyped SNPs, we found that rs60106404 (P = 2.38 × 10
) located at SPATS2L reached the genome-wide significance level, and 216 SNPs exceeded the level of a suggestive association. We found 1007 genes nominally associated with the FPG level (P < 0.05), including SPATS2L, KCNK5, ADCY5, PCSK1, PTPRA, and SLC26A11. Moreover, C1orf74 (P = 0.014) and SLC26A11 (P = 0.021) were differentially expressed between patients with impaired fasting glucose and healthy controls. Some important enriched biological pathways, such as β-alanine metabolism, regulation of insulin secretion, glucagon signaling in metabolic regulation, IL-1 receptor pathway, signaling by platelet derived growth factor, cysteine and methionine metabolism pathway, were identified.
The FPG level is highly heritable in the Chinese population, and genetic variants are significantly involved in regulatory domains, functional genes and biological pathways that mediate FPG levels. This study provides important clues for further elucidating the molecular mechanism of glucose homeostasis and discovering new diagnostic biomarkers and therapeutic targets for diabetes.