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Genome-wide Analysis Identifies Locus associated with Parathyroid Hormone Levels

Matana, Antonela; Brdar, Dubravka; Torlak, Vesela; Popović, Marijana; Gunjača, Ivana; Polašek, Ozren; Boraska Perica, Vesna; Barbalić, Maja; Punda, Ante; Hayward, Caroline; Zemunik, Tatijana
Genome-wide Analysis Identifies Locus associated with Parathyroid Hormone Levels // International Journal of Bioengineering and Life Sciences
Bangkok, Tajland, 2017. str. - (predavanje, međunarodna recenzija, sažetak, znanstveni)

Genome-wide Analysis Identifies Locus associated with Parathyroid Hormone Levels

Matana, Antonela ; Brdar, Dubravka ; Torlak, Vesela ; Popović, Marijana ; Gunjača, Ivana ; Polašek, Ozren ; Boraska Perica, Vesna ; Barbalić, Maja ; Punda, Ante ; Hayward, Caroline ; Zemunik, Tatijana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

International Journal of Bioengineering and Life Sciences / - , 2017

ICHG 2017: 19th International Conference on Human Genetics

Mjesto i datum
Bangkok, Tajland, 18-19.12.2017

Vrsta sudjelovanja

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Genome-wide association analysis ; Parathyroid hormone

Abstract— Parathyroid hormone (PTH) plays a critical role in regulation of bone mineral metabolism and calcium homeostasis. Higher PTH levels are associated with heart failure, hypertension, coronary artery disease, cardiovascular mortality and poorer bone health. A twin study estimated that 60% of variation in PTH concentrations is genetically determined. Only one GWAS of PTH concentration has been reported to date. Identified loci explained 4.5% of the variance in circulating PTH, suggesting that additional genetic variants remain undiscovered. Therefore, the aim of this study was to identify novel genetic variants associated with PTH levels in a general population. We have performed a GWAS meta-analysis on 2596 individuals originating from three Croatian cohorts: City of Split and the Islands of Korčula and Vis, within a large- scale project of “10, 001 Dalmatians”. A total of 7 411 206 variants, imputed using the 1000 Genomes reference panel, with minor allele frequency ≥ 1% and Rsq ≥ 0.5 were analyzed for association. GWAS within each data set was performed under an additive model, controlling for age, gender and relatedness. Meta-analysis was conducted using the inverse-variance fixed- effects method. Furthermore, to identify sex- specific effects we have conducted GWAS meta- analyses analyzing males and females separately. In addition, we have performed biological pathway analysis. Four SNPs, representing one locus, reached genome-wide significance. The most significant SNP was rs11099476 on chromosome 4 (P=1.15x10- 8), which explained 1.14 % of the variance in PTH. The SNP is located near the protein coding gene RASGEF1B. Additionally, we detected suggestive association with SNPs, rs77178854 located on chromosome 2 in the DPP10 gene (P=2.46x10-7) and rs481121 located on chromosome 1 (P=3.58x10-7) near the GRIK1 gene. One of the top hits detected in the main meta- analysis, intron variant rs77178854 located within DPP10 gene, reached genome-wide significance in females (P=2.21x10-9). No single locus was identified in the meta- analysis in males. Fifteen biological pathways were functionally enriched at a P<0.01, including muscle contraction, ion homeostasis and cardiac conduction as the most significant pathways. RASGEF1B is the guanine nucleotide exchange factor, known to be associated with height, bone density and hip. DPP10 encodes a membrane protein that is a member of the serine proteases family, which binds specific voltage- gated potassium channels and alters their expression and biophysical properties. In conclusion, we identified 2 novel loci associated with PTH levels in a general population, providing us with further insights into the genetics of this complex trait.

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