Family-based genome-wide association study of south Indian pedigrees supports WNT7B as a central corneal thickness locus

Bao Jian Fan, Xueli Chen, Nisha Sondhi, P. Ferdinamarie Sharmila, Nagasamy Soumittra, Sarangapani Sripriya, Srinivasan Sacikala, Rashima Asokan, David S. Friedman, Louis R. Pasquale, X. Raymond Gao, Lingam Vijaya, Jessica Cooke Bailey, Veronique Vitart, Stuart Macgregor, Christopher J. Hammond, Chiea Chuen Khor, Jonathan L. Haines, Ronnie George, Janey L. WiggsR. Rand Allingham, X. Raymond Gao, Jim Gauderman, Michael Hauser, Jerome I. Rotter, Rohit Varma, Janey Wiggs, Tin Aung, Kathryn P. Burdon, Ching Yu Cheng, Jamie E. Craig, Angela J. Cree, Puya Gharahkhani, Alex W. Hewitt, René Höhn, Pirro Hysi, Adriana I. Iglesias Gonzalez, Jost Jonas, Anthony Khawaja, Chiea Cheun Khor, Caroline C.W. Klaver, Francesca Pasutto, Stuart Macgregor, David Mackey, Paul Mitchell, Aniket Mishra, Calvin Pang, Louis R. Pasquale, Francesca Pasutto, Henriette Springelkamp, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Cornelia M. van Duijn, Ananth Viswanathan, Veronique Vitart, Janey L. Wiggs, Robert Wojciechowski, Tien Wong, Terri L. Young, Tanja Zeller, Rand Allingham, Murray Brilliant, Don Budenz, Jessica Cooke Bailey, John Fingert, Douglas Gaasterland, Teresa Gaasterland, Jonathan L. Haines, Michael Hauser, Rob Igo, Jae Hee Kang, Peter Kraft, Richard Lee, Paul Lichter, Yutao Liu, Syoko Moroi, Louis R. Pasquale, Anthony Realini, Doug Rhee, Julia R. Richards, Robert Ritch, Joel Schuman, William K. Scott, Arthur J Sit, Arthur Sit, Douglas Vollrath, Robert N. Weinreb, Janey L. Wiggs, Gadi Wollstein, Don Zack

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

Original languageEnglish (US)
Pages (from-to)2495-2502
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number6
DOIs
StatePublished - May 1 2018

Fingerprint

Genome-Wide Association Study
Pedigree
Single Nucleotide Polymorphism
Hispanic Americans
Population
Myopia
Introns
Meta-Analysis
India
Confidence Intervals

Keywords

  • Cornea central thickness
  • Genetic association
  • Ocular PheWAS
  • Quantitative trait
  • WNT7B

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Family-based genome-wide association study of south Indian pedigrees supports WNT7B as a central corneal thickness locus. / Fan, Bao Jian; Chen, Xueli; Sondhi, Nisha; Sharmila, P. Ferdinamarie; Soumittra, Nagasamy; Sripriya, Sarangapani; Sacikala, Srinivasan; Asokan, Rashima; Friedman, David S.; Pasquale, Louis R.; Gao, X. Raymond; Vijaya, Lingam; Bailey, Jessica Cooke; Vitart, Veronique; Macgregor, Stuart; Hammond, Christopher J.; Khor, Chiea Chuen; Haines, Jonathan L.; George, Ronnie; Wiggs, Janey L.; Allingham, R. Rand; Gao, X. Raymond; Gauderman, Jim; Hauser, Michael; Rotter, Jerome I.; Varma, Rohit; Wiggs, Janey; Aung, Tin; Burdon, Kathryn P.; Cheng, Ching Yu; Craig, Jamie E.; Cree, Angela J.; Gharahkhani, Puya; Hewitt, Alex W.; Höhn, René; Hysi, Pirro; Iglesias Gonzalez, Adriana I.; Jonas, Jost; Khawaja, Anthony; Khor, Chiea Cheun; Klaver, Caroline C.W.; Pasutto, Francesca; Macgregor, Stuart; Mackey, David; Mitchell, Paul; Mishra, Aniket; Pang, Calvin; Pasquale, Louis R.; Pasutto, Francesca; Springelkamp, Henriette; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; van Duijn, Cornelia M.; Viswanathan, Ananth; Vitart, Veronique; Wiggs, Janey L.; Wojciechowski, Robert; Wong, Tien; Young, Terri L.; Zeller, Tanja; Allingham, Rand; Brilliant, Murray; Budenz, Don; Bailey, Jessica Cooke; Fingert, John; Gaasterland, Douglas; Gaasterland, Teresa; Haines, Jonathan L.; Hauser, Michael; Igo, Rob; Kang, Jae Hee; Kraft, Peter; Lee, Richard; Lichter, Paul; Liu, Yutao; Moroi, Syoko; Pasquale, Louis R.; Realini, Anthony; Rhee, Doug; Richards, Julia R.; Ritch, Robert; Schuman, Joel; Scott, William K.; Sit, Arthur J; Sit, Arthur; Vollrath, Douglas; Weinreb, Robert N.; Wiggs, Janey L.; Wollstein, Gadi; Zack, Don.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 6, 01.05.2018, p. 2495-2502.

Research output: Contribution to journalArticle

Fan, BJ, Chen, X, Sondhi, N, Sharmila, PF, Soumittra, N, Sripriya, S, Sacikala, S, Asokan, R, Friedman, DS, Pasquale, LR, Gao, XR, Vijaya, L, Bailey, JC, Vitart, V, Macgregor, S, Hammond, CJ, Khor, CC, Haines, JL, George, R, Wiggs, JL, Allingham, RR, Gao, XR, Gauderman, J, Hauser, M, Rotter, JI, Varma, R, Wiggs, J, Aung, T, Burdon, KP, Cheng, CY, Craig, JE, Cree, AJ, Gharahkhani, P, Hewitt, AW, Höhn, R, Hysi, P, Iglesias Gonzalez, AI, Jonas, J, Khawaja, A, Khor, CC, Klaver, CCW, Pasutto, F, Macgregor, S, Mackey, D, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Pasutto, F, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, van Duijn, CM, Viswanathan, A, Vitart, V, Wiggs, JL, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Allingham, R, Brilliant, M, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hauser, M, Igo, R, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pasquale, LR, Realini, A, Rhee, D, Richards, JR, Ritch, R, Schuman, J, Scott, WK, Sit, AJ, Sit, A, Vollrath, D, Weinreb, RN, Wiggs, JL, Wollstein, G & Zack, D 2018, 'Family-based genome-wide association study of south Indian pedigrees supports WNT7B as a central corneal thickness locus', Investigative Ophthalmology and Visual Science, vol. 59, no. 6, pp. 2495-2502. https://doi.org/10.1167/iovs.17-23536
Fan, Bao Jian ; Chen, Xueli ; Sondhi, Nisha ; Sharmila, P. Ferdinamarie ; Soumittra, Nagasamy ; Sripriya, Sarangapani ; Sacikala, Srinivasan ; Asokan, Rashima ; Friedman, David S. ; Pasquale, Louis R. ; Gao, X. Raymond ; Vijaya, Lingam ; Bailey, Jessica Cooke ; Vitart, Veronique ; Macgregor, Stuart ; Hammond, Christopher J. ; Khor, Chiea Chuen ; Haines, Jonathan L. ; George, Ronnie ; Wiggs, Janey L. ; Allingham, R. Rand ; Gao, X. Raymond ; Gauderman, Jim ; Hauser, Michael ; Rotter, Jerome I. ; Varma, Rohit ; Wiggs, Janey ; Aung, Tin ; Burdon, Kathryn P. ; Cheng, Ching Yu ; Craig, Jamie E. ; Cree, Angela J. ; Gharahkhani, Puya ; Hewitt, Alex W. ; Höhn, René ; Hysi, Pirro ; Iglesias Gonzalez, Adriana I. ; Jonas, Jost ; Khawaja, Anthony ; Khor, Chiea Cheun ; Klaver, Caroline C.W. ; Pasutto, Francesca ; Macgregor, Stuart ; Mackey, David ; Mitchell, Paul ; Mishra, Aniket ; Pang, Calvin ; Pasquale, Louis R. ; Pasutto, Francesca ; Springelkamp, Henriette ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; van Duijn, Cornelia M. ; Viswanathan, Ananth ; Vitart, Veronique ; Wiggs, Janey L. ; Wojciechowski, Robert ; Wong, Tien ; Young, Terri L. ; Zeller, Tanja ; Allingham, Rand ; Brilliant, Murray ; Budenz, Don ; Bailey, Jessica Cooke ; Fingert, John ; Gaasterland, Douglas ; Gaasterland, Teresa ; Haines, Jonathan L. ; Hauser, Michael ; Igo, Rob ; Kang, Jae Hee ; Kraft, Peter ; Lee, Richard ; Lichter, Paul ; Liu, Yutao ; Moroi, Syoko ; Pasquale, Louis R. ; Realini, Anthony ; Rhee, Doug ; Richards, Julia R. ; Ritch, Robert ; Schuman, Joel ; Scott, William K. ; Sit, Arthur J ; Sit, Arthur ; Vollrath, Douglas ; Weinreb, Robert N. ; Wiggs, Janey L. ; Wollstein, Gadi ; Zack, Don. / Family-based genome-wide association study of south Indian pedigrees supports WNT7B as a central corneal thickness locus. In: Investigative Ophthalmology and Visual Science. 2018 ; Vol. 59, No. 6. pp. 2495-2502.
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abstract = "Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95{\%} confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95{\%} CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.",
keywords = "Cornea central thickness, Genetic association, Ocular PheWAS, Quantitative trait, WNT7B",
author = "Fan, {Bao Jian} and Xueli Chen and Nisha Sondhi and Sharmila, {P. Ferdinamarie} and Nagasamy Soumittra and Sarangapani Sripriya and Srinivasan Sacikala and Rashima Asokan and Friedman, {David S.} and Pasquale, {Louis R.} and Gao, {X. Raymond} and Lingam Vijaya and Bailey, {Jessica Cooke} and Veronique Vitart and Stuart Macgregor and Hammond, {Christopher J.} and Khor, {Chiea Chuen} and Haines, {Jonathan L.} and Ronnie George and Wiggs, {Janey L.} and Allingham, {R. Rand} and Gao, {X. Raymond} and Jim Gauderman and Michael Hauser and Rotter, {Jerome I.} and Rohit Varma and Janey Wiggs and Tin Aung and Burdon, {Kathryn P.} and Cheng, {Ching Yu} and Craig, {Jamie E.} and Cree, {Angela J.} and Puya Gharahkhani and Hewitt, {Alex W.} and Ren{\'e} H{\"o}hn and Pirro Hysi and {Iglesias Gonzalez}, {Adriana I.} and Jost Jonas and Anthony Khawaja and Khor, {Chiea Cheun} and Klaver, {Caroline C.W.} and Francesca Pasutto and Stuart Macgregor and David Mackey and Paul Mitchell and Aniket Mishra and Calvin Pang and Pasquale, {Louis R.} and Francesca Pasutto and Henriette Springelkamp and Gudmar Thorleifsson and Unnur Thorsteinsdottir and {van Duijn}, {Cornelia M.} and Ananth Viswanathan and Veronique Vitart and Wiggs, {Janey L.} and Robert Wojciechowski and Tien Wong and Young, {Terri L.} and Tanja Zeller and Rand Allingham and Murray Brilliant and Don Budenz and Bailey, {Jessica Cooke} and John Fingert and Douglas Gaasterland and Teresa Gaasterland and Haines, {Jonathan L.} and Michael Hauser and Rob Igo and Kang, {Jae Hee} and Peter Kraft and Richard Lee and Paul Lichter and Yutao Liu and Syoko Moroi and Pasquale, {Louis R.} and Anthony Realini and Doug Rhee and Richards, {Julia R.} and Robert Ritch and Joel Schuman and Scott, {William K.} and Sit, {Arthur J} and Arthur Sit and Douglas Vollrath and Weinreb, {Robert N.} and Wiggs, {Janey L.} and Gadi Wollstein and Don Zack",
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language = "English (US)",
volume = "59",
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journal = "Investigative Ophthalmology and Visual Science",
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TY - JOUR

T1 - Family-based genome-wide association study of south Indian pedigrees supports WNT7B as a central corneal thickness locus

AU - Fan, Bao Jian

AU - Chen, Xueli

AU - Sondhi, Nisha

AU - Sharmila, P. Ferdinamarie

AU - Soumittra, Nagasamy

AU - Sripriya, Sarangapani

AU - Sacikala, Srinivasan

AU - Asokan, Rashima

AU - Friedman, David S.

AU - Pasquale, Louis R.

AU - Gao, X. Raymond

AU - Vijaya, Lingam

AU - Bailey, Jessica Cooke

AU - Vitart, Veronique

AU - Macgregor, Stuart

AU - Hammond, Christopher J.

AU - Khor, Chiea Chuen

AU - Haines, Jonathan L.

AU - George, Ronnie

AU - Wiggs, Janey L.

AU - Allingham, R. Rand

AU - Gao, X. Raymond

AU - Gauderman, Jim

AU - Hauser, Michael

AU - Rotter, Jerome I.

AU - Varma, Rohit

AU - Wiggs, Janey

AU - Aung, Tin

AU - Burdon, Kathryn P.

AU - Cheng, Ching Yu

AU - Craig, Jamie E.

AU - Cree, Angela J.

AU - Gharahkhani, Puya

AU - Hewitt, Alex W.

AU - Höhn, René

AU - Hysi, Pirro

AU - Iglesias Gonzalez, Adriana I.

AU - Jonas, Jost

AU - Khawaja, Anthony

AU - Khor, Chiea Cheun

AU - Klaver, Caroline C.W.

AU - Pasutto, Francesca

AU - Macgregor, Stuart

AU - Mackey, David

AU - Mitchell, Paul

AU - Mishra, Aniket

AU - Pang, Calvin

AU - Pasquale, Louis R.

AU - Pasutto, Francesca

AU - Springelkamp, Henriette

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - van Duijn, Cornelia M.

AU - Viswanathan, Ananth

AU - Vitart, Veronique

AU - Wiggs, Janey L.

AU - Wojciechowski, Robert

AU - Wong, Tien

AU - Young, Terri L.

AU - Zeller, Tanja

AU - Allingham, Rand

AU - Brilliant, Murray

AU - Budenz, Don

AU - Bailey, Jessica Cooke

AU - Fingert, John

AU - Gaasterland, Douglas

AU - Gaasterland, Teresa

AU - Haines, Jonathan L.

AU - Hauser, Michael

AU - Igo, Rob

AU - Kang, Jae Hee

AU - Kraft, Peter

AU - Lee, Richard

AU - Lichter, Paul

AU - Liu, Yutao

AU - Moroi, Syoko

AU - Pasquale, Louis R.

AU - Realini, Anthony

AU - Rhee, Doug

AU - Richards, Julia R.

AU - Ritch, Robert

AU - Schuman, Joel

AU - Scott, William K.

AU - Sit, Arthur J

AU - Sit, Arthur

AU - Vollrath, Douglas

AU - Weinreb, Robert N.

AU - Wiggs, Janey L.

AU - Wollstein, Gadi

AU - Zack, Don

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

AB - Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

KW - Cornea central thickness

KW - Genetic association

KW - Ocular PheWAS

KW - Quantitative trait

KW - WNT7B

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U2 - 10.1167/iovs.17-23536

DO - 10.1167/iovs.17-23536

M3 - Article

C2 - 29847655

AN - SCOPUS:85047451548

VL - 59

SP - 2495

EP - 2502

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 6

ER -