Genome-wide association study identifies a susceptibility locus for comitant esotropia and suggests a parent-of-origin effect

Strabismus Genetics Research Consortium

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

PURPOSE. To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. METHODS. White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case–control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. RESULTS. A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 ☓ 1009) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 ☓ 1011). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 ☓ 1008), an intergenic SNP on chromosome 1p31.1. CONCLUSIONS. This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.

Original languageEnglish
Pages (from-to)4054-4064
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number10
DOIs
Publication statusPublished - 1 Aug 2018

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Esotropia
Genome-Wide Association Study
Odds Ratio
Meta-Analysis
Strabismus
Single Nucleotide Polymorphism
Chromosomes, Human, Pair 21
Tryptophan
Introns
Linear Models
Chromosomes
Incidence
Population
Proteins

Cite this

@article{6dea04efc4ab4d56b76a28945eeb3199,
title = "Genome-wide association study identifies a susceptibility locus for comitant esotropia and suggests a parent-of-origin effect",
abstract = "PURPOSE. To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. METHODS. White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case–control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. RESULTS. A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 ☓ 1009) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 ☓ 1011). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 ☓ 1008), an intergenic SNP on chromosome 1p31.1. CONCLUSIONS. This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.",
keywords = "Esotropia, Genome-wide association study, Parent-of-origin, Strabismus, WRB",
author = "{Strabismus Genetics Research Consortium} and Sherin Shaaban and Sarah Mackinnon and Caroline Andrews and Staffieri, {Sandra E.} and Maconachie, {Gail D.E.} and Chan, {Wai Man} and Whitman, {Mary C.} and Morton, {Sarah U.} and Seyhan Yazar and Stuart Macgregor and Elder, {James E.} and Traboulsi, {Elias I.} and Irene Gottlob and Hewitt, {Alex W.} and Hunter, {David G.} and Mackey, {David A.} and Engle, {Elizabeth C.} and Anna Baglieri and Brenda Barry and Sarah Bekele and Breau, {Sarah E.} and Kimberley Chan and Frances Corkin and Dagi, {Linda R.} and Alexandra Elliott and Janet Esligar and Caroline Fang and Fulton, {Anne B.} and Gena Heidary and Suzanne Johnston and Melanie Kazlas and Ledoux, {Danielle M.} and Levy, {Richard L.} and Mantagos, {Iason S.} and Miller, {Kathryn B.} and Monte Mills and Darren Oystreck and Petersen, {Christina S.} and Petersen, {Robert A.} and Pierce, {Carrie E.} and Aparna Raghuram and Richard Robb and Sandoval, {Josephine C.} and Sonia Sethee and Shah, {Ankoor S.} and Smith, {Lois E.H.} and Melissa Toffoloni and Vanderveen, {Deborah K.} and Sarah Whitecross and Wong, {Rupa K.} and Carolyn Wu and Julie Barbour and Linda Clarke and Dondey, {Joanne C.} and Maree Flaherty and John Grigg and Kate Hanman and Michael Haybittel and Jamieson, {Robyn V.} and Kearns, {Lisa S.} and Lionel Kowal and Lam, {Geoffrey C.} and Joon, {Troy Lim} and John McKenzie and Loren Rose and Ruddle, {Jonathan B.} and Lindsey Scotter and Sinclair, {Neil E.} and Colleen Wilkinson and Robin Wilkinson and Viral Sheth and Thomas, {Mervyn G.}",
year = "2018",
month = "8",
day = "1",
doi = "10.1167/iovs.18-24082",
language = "English",
volume = "59",
pages = "4054--4064",
journal = "Investigative Ophthalmology & Visual Science (IOVS)",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology (ARVO)",
number = "10",

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Genome-wide association study identifies a susceptibility locus for comitant esotropia and suggests a parent-of-origin effect. / Strabismus Genetics Research Consortium.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 10, 01.08.2018, p. 4054-4064.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study identifies a susceptibility locus for comitant esotropia and suggests a parent-of-origin effect

AU - Strabismus Genetics Research Consortium

AU - Shaaban, Sherin

AU - Mackinnon, Sarah

AU - Andrews, Caroline

AU - Staffieri, Sandra E.

AU - Maconachie, Gail D.E.

AU - Chan, Wai Man

AU - Whitman, Mary C.

AU - Morton, Sarah U.

AU - Yazar, Seyhan

AU - Macgregor, Stuart

AU - Elder, James E.

AU - Traboulsi, Elias I.

AU - Gottlob, Irene

AU - Hewitt, Alex W.

AU - Hunter, David G.

AU - Mackey, David A.

AU - Engle, Elizabeth C.

AU - Baglieri, Anna

AU - Barry, Brenda

AU - Bekele, Sarah

AU - Breau, Sarah E.

AU - Chan, Kimberley

AU - Corkin, Frances

AU - Dagi, Linda R.

AU - Elliott, Alexandra

AU - Esligar, Janet

AU - Fang, Caroline

AU - Fulton, Anne B.

AU - Heidary, Gena

AU - Johnston, Suzanne

AU - Kazlas, Melanie

AU - Ledoux, Danielle M.

AU - Levy, Richard L.

AU - Mantagos, Iason S.

AU - Miller, Kathryn B.

AU - Mills, Monte

AU - Oystreck, Darren

AU - Petersen, Christina S.

AU - Petersen, Robert A.

AU - Pierce, Carrie E.

AU - Raghuram, Aparna

AU - Robb, Richard

AU - Sandoval, Josephine C.

AU - Sethee, Sonia

AU - Shah, Ankoor S.

AU - Smith, Lois E.H.

AU - Toffoloni, Melissa

AU - Vanderveen, Deborah K.

AU - Whitecross, Sarah

AU - Wong, Rupa K.

AU - Wu, Carolyn

AU - Barbour, Julie

AU - Clarke, Linda

AU - Dondey, Joanne C.

AU - Flaherty, Maree

AU - Grigg, John

AU - Hanman, Kate

AU - Haybittel, Michael

AU - Jamieson, Robyn V.

AU - Kearns, Lisa S.

AU - Kowal, Lionel

AU - Lam, Geoffrey C.

AU - Joon, Troy Lim

AU - McKenzie, John

AU - Rose, Loren

AU - Ruddle, Jonathan B.

AU - Scotter, Lindsey

AU - Sinclair, Neil E.

AU - Wilkinson, Colleen

AU - Wilkinson, Robin

AU - Sheth, Viral

AU - Thomas, Mervyn G.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - PURPOSE. To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. METHODS. White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case–control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. RESULTS. A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 ☓ 1009) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 ☓ 1011). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 ☓ 1008), an intergenic SNP on chromosome 1p31.1. CONCLUSIONS. This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.

AB - PURPOSE. To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. METHODS. White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case–control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. RESULTS. A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 ☓ 1009) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 ☓ 1011). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 ☓ 1008), an intergenic SNP on chromosome 1p31.1. CONCLUSIONS. This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.

KW - Esotropia

KW - Genome-wide association study

KW - Parent-of-origin

KW - Strabismus

KW - WRB

UR - http://www.scopus.com/inward/record.url?scp=85051665575&partnerID=8YFLogxK

U2 - 10.1167/iovs.18-24082

DO - 10.1167/iovs.18-24082

M3 - Article

VL - 59

SP - 4054

EP - 4064

JO - Investigative Ophthalmology & Visual Science (IOVS)

JF - Investigative Ophthalmology & Visual Science (IOVS)

SN - 0146-0404

IS - 10

ER -