GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans

Geetha Chittoor, Jack W. Kent, Marcio Almeida, Sobha Puppala, Vidya S. Farook, Shelley A. Cole, Karin Haack, Harald H H Göring, Jean W. MacCluer, Joanne E. Curran, Melanie A. Carless, Matthew P. Johnson, Eric K. Moses, Laura Almasy, Michael C. Mahaney, Donna M Lehman, Ravindranath Duggirala, Anthony G. Comuzzie, John Blangero, Venkata Saroja Voruganti

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. Results: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h 2=0.50±0.05, p-35), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD=4.9, p-5) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p-7; minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. Conclusion: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.

Original languageEnglish (US)
Article number276
JournalBMC Genomics
Volume17
Issue number1
DOIs
StatePublished - Apr 2 2016

Fingerprint

Contactins
Inositol 1,4,5-Trisphosphate Receptors
Genome-Wide Association Study
Uric Acid
Serum
Chromosomes
Rho Guanine Nucleotide Exchange Factors
Genetic Loci
Kidney Calculi
Gout
Gallbladder
Chronic Renal Insufficiency
Gene Frequency
Multiple Sclerosis
Single Nucleotide Polymorphism
Parkinson Disease
Linear Models
Alzheimer Disease
Cardiovascular Diseases
Joints

Keywords

  • CNTN4
  • Family-based study
  • ITPR1
  • Joint linkage/association approach

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Chittoor, G., Kent, J. W., Almeida, M., Puppala, S., Farook, V. S., Cole, S. A., ... Voruganti, V. S. (2016). GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. BMC Genomics, 17(1), [276]. https://doi.org/10.1186/s12864-016-2594-5

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. / Chittoor, Geetha; Kent, Jack W.; Almeida, Marcio; Puppala, Sobha; Farook, Vidya S.; Cole, Shelley A.; Haack, Karin; Göring, Harald H H; MacCluer, Jean W.; Curran, Joanne E.; Carless, Melanie A.; Johnson, Matthew P.; Moses, Eric K.; Almasy, Laura; Mahaney, Michael C.; Lehman, Donna M; Duggirala, Ravindranath; Comuzzie, Anthony G.; Blangero, John; Voruganti, Venkata Saroja.

In: BMC Genomics, Vol. 17, No. 1, 276, 02.04.2016.

Research output: Contribution to journalArticle

Chittoor, G, Kent, JW, Almeida, M, Puppala, S, Farook, VS, Cole, SA, Haack, K, Göring, HHH, MacCluer, JW, Curran, JE, Carless, MA, Johnson, MP, Moses, EK, Almasy, L, Mahaney, MC, Lehman, DM, Duggirala, R, Comuzzie, AG, Blangero, J & Voruganti, VS 2016, 'GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans', BMC Genomics, vol. 17, no. 1, 276. https://doi.org/10.1186/s12864-016-2594-5
Chittoor, Geetha ; Kent, Jack W. ; Almeida, Marcio ; Puppala, Sobha ; Farook, Vidya S. ; Cole, Shelley A. ; Haack, Karin ; Göring, Harald H H ; MacCluer, Jean W. ; Curran, Joanne E. ; Carless, Melanie A. ; Johnson, Matthew P. ; Moses, Eric K. ; Almasy, Laura ; Mahaney, Michael C. ; Lehman, Donna M ; Duggirala, Ravindranath ; Comuzzie, Anthony G. ; Blangero, John ; Voruganti, Venkata Saroja. / GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. In: BMC Genomics. 2016 ; Vol. 17, No. 1.
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abstract = "Background: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. Results: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h 2=0.50±0.05, p-35), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD=4.9, p-5) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p-7; minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. Conclusion: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.",
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T1 - GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans

AU - Chittoor, Geetha

AU - Kent, Jack W.

AU - Almeida, Marcio

AU - Puppala, Sobha

AU - Farook, Vidya S.

AU - Cole, Shelley A.

AU - Haack, Karin

AU - Göring, Harald H H

AU - MacCluer, Jean W.

AU - Curran, Joanne E.

AU - Carless, Melanie A.

AU - Johnson, Matthew P.

AU - Moses, Eric K.

AU - Almasy, Laura

AU - Mahaney, Michael C.

AU - Lehman, Donna M

AU - Duggirala, Ravindranath

AU - Comuzzie, Anthony G.

AU - Blangero, John

AU - Voruganti, Venkata Saroja

PY - 2016/4/2

Y1 - 2016/4/2

N2 - Background: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. Results: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h 2=0.50±0.05, p-35), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD=4.9, p-5) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p-7; minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. Conclusion: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.

AB - Background: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. Results: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h 2=0.50±0.05, p-35), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD=4.9, p-5) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p-7; minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. Conclusion: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.

KW - CNTN4

KW - Family-based study

KW - ITPR1

KW - Joint linkage/association approach

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