Genome-wide association study identifies a novel susceptibility gene for serum TSH levels in Chinese populations.
Thyroid-stimulating hormone (TSH) is a sensitive indicator of thyroid function. High and low TSH levels reflect hypothyroidism and hyperthyroidism, respectively. Even within the normal range, small differences in TSH levels, on the order of 0.5-1.0 mU/l, are associated with significant differences in blood pressure, BMI, dyslipidemia, risk of atrial fibrillation and atherosclerosis. Most of the variance in TSH levels is thought to be genetically influenced. We conducted a genome-wide association study of TSH levels in 1346 Chinese Han individuals. In the replication study, we genotyped four candidate SNPs with the top association signals in an independent isolated Chinese She cohort (n = 3235). We identified a novel serum TSH susceptibility locus within XKR4 at 8q12.1 (rs2622590, Pcombined = 2.21 × 10(-10)), and we confirmed two previously reported TSH susceptibility loci near FOXE1 at 9q22.33 and near CAPZB at 1p36.13, respectively. The rs2622590_T allele at XKR4 and the rs925489_C allele near FOXE1 were correlated with low TSH levels and were found to be nominally associated to patients with papillary thyroid carcinoma (PTC) (OR = 1.41, P= 0.014 for rs2622590_T, and OR = 1.61, P= 0.030 for rs925489_C). The rs2622590 and rs925489 genotypes were also correlated with the expression levels of FOXE1 and XKR4, respectively, in PTC tissues (P = 2.41 × 10(-4) and P= 0.02). Our findings suggest that the SNPs in XKR4 and near FOXE1 are involved in the regulation of TSH levels.
State Key Laboratory of Medical Genomics and Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai 200025, China.
Ming
M
Zhan
Department of Endocrinology, Fujian Provincial Hospital, Fujian Medical University, Fuzhou 350001, China.
Gang
G
Chen
State Key Laboratory of Medical Genomics and.
Chun-Ming
CM
Pan
Shanghai Center for Systems Biomedicine, SJTU, Shanghai 200240, China.
Zhao-Hui
ZH
Gu
State Key Laboratory of Medical Genomics and Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai 200025, China.
Shuang-Xia
SX
Zhao
State Key Laboratory of Medical Genomics and Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai 200025, China.
Wei
W
Liu
State Key Laboratory of Medical Genomics and.
Hai-Ning
HN
Wang
State Key Laboratory of Medical Genomics and.
Xiao-Ping
XP
Ye
State Key Laboratory of Medical Genomics and.
Hui-Jun
HJ
Xie
State Key Laboratory of Medical Genomics and Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai 200025, China.
Sha-Sha
SS
Yu
Department of Endocrinology, The Central Hospital of Xuzhou Affiliated to Xuzhou Medical College, Xuzhou, Jiangsu Province 221109, China.
Jun
J
Liang
Department of Endocrinology, Linyi People's Hospital, Linyi, Shandong Province 276003, China.
Guan-Qi
GQ
Gao
Department of Endocrinology, The Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu Province 213001, China.
Guo-Yue
GY
Yuan
Department of Endocrinology, The First Hospital Affiliated to Bengbu Medical College, Bengbu, Anhui Province 233004, China.
Xiao-Mei
XM
Zhang
Department of Endocrinology, The First Hospital Affiliated to Anhui Medical University, Hefei, Anhui Province 230022, China.
Chun-Lin
CL
Zuo
Department of Endocrinology, The Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, China.
Bin
B
Su
Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center, Shanghai 201303, China.
Wei
W
Huang
State Key Laboratory of Medical Genomics and Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai 200025, China.
Guang
G
Ning
State Key Laboratory of Medical Genomics and.
Sai-Juan
SJ
Chen
Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai 200025, China.
Jia-Lun
JL
Chen
State Key Laboratory of Medical Genomics and Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai 200025, China huaidong_s1966@163.com.
Huai-Dong
HD
Song
D051017:Apoptosis Regulatory Proteins; D044466:Asian People / Q000235:genetics; D051347:CapZ Actin Capping Protein / Q000235:genetics; D002277:Carcinoma / Q000235:genetics*; D002291:Carcinoma, Papillary; D002681:China; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D008565:Membrane Proteins; D026901:Membrane Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*; D013972:Thyrotropin / Q000097:blood* / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C000598253:CAPZB protein, human; D051347:CapZ Actin Capping Protein; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C573063:XKR4 protein, human; D013972:Thyrotropin