Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
20395239
TITLE
Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.
ABSTRACT
Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P=6.2x10(-10), near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-7), in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P=0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.
DATE PUBLISHED
2010 Jul 01
HISTORY
PUBSTATUS PUBSTATUSDATE
entrez 2010/04/17 06:00
pubmed 2010/04/17 06:00
medline 2010/09/21 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Macgregor S Macgregor Stuart S Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia.
Hewitt AW Hewitt Alex W AW
Hysi PG Hysi Pirro G PG
Ruddle JB Ruddle Jonathan B JB
Medland SE Medland Sarah E SE
Henders AK Henders Anjali K AK
Gordon SD Gordon Scott D SD
Andrew T Andrew Toby T
McEvoy B McEvoy Brian B
Sanfilippo PG Sanfilippo Paul G PG
Carbonaro F Carbonaro Francis F
Tah V Tah Vikas V
Li YJ Li Yi Ju YJ
Bennett SL Bennett Sonya L SL
Craig JE Craig Jamie E JE
Montgomery GW Montgomery Grant W GW
Tran-Viet KN Tran-Viet Khanh-Nhat KN
Brown NL Brown Nadean L NL
Spector TD Spector Timothy D TD
Martin NG Martin Nicholas G NG
Young TL Young Terri L TL
Hammond CJ Hammond Christopher J CJ
Mackey DA Mackey David A DA
INVESTIGATORS
JOURNAL
VOLUME: 19
ISSUE: 13
TITLE: Human molecular genetics
ISOABBREVIATION: Hum Mol Genet
YEAR: 2010
MONTH: Jul
DAY: 01
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2083
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
1R01EY013612 NEI NIH HHS United States
G20234 Biotechnology and Biological Sciences Research Council United Kingdom
1R01EY018246 NEI NIH HHS United States
Medical Research Council United Kingdom
R01 EY013612 NEI NIH HHS United States
R01 EY013612-10 NEI NIH HHS United States
Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Adult
Aged
Aged, 80 and over
Australia
Basic Helix-Loop-Helix Transcription Factors genetics
Blindness genetics
Child genetics
Child, Preschool genetics
Genome-Wide Association Study genetics
Humans genetics
Membrane Proteins genetics
Middle Aged genetics
Optic Disk genetics
Optic Nerve pathology
Polymorphism, Single Nucleotide genetics
Twins genetics
United Kingdom genetics
Young Adult genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 ATOH7 protein, human
0 Basic Helix-Loop-Helix Transcription Factors
0 Membrane Proteins
0 RFTN1 protein, human
OTHER ID's
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