Genomewide linkage scans for ocular refraction and meta-analysis of four populations in the Myopia Family Study
Robert J Wojciechowski 1*,
Dwight Stambolian 2,
Elise B Ciner 3,
Grace Ibay 1,
Taura N Holmes 1,
and
Joan E. Bailey-Wilson 1
1 Inherited Disease Research Branch, NHGRI, Baltimore, Maryland, United States
2 Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
3 Infant Vision Service, Pennsylvania College of Optometry, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: robwoj{at}mail.nih.gov.
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Abstract |
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Purpose: We performed genomewide linkage scans in Caucasian (CAUC) and Old Order Amish (OOA) families to identify genomic regions containing genes responsible for refractive error control. We also performed a meta-analysis by combining these results with our previous linkage results from Ashkenazi Jewish (ASHK) and African American (AFRAM) families.
Methods: We recruited 271 CAUC and 411 OOA participants (36 and 61 families, respectively) to participate in the Myopia Family Study. Recruitment criteria were designed to enrich the sample for multiplex myopic families. Genomewide, model-free, multipoint linkage analyses were performed separately for each population using >370 microsatellite markers. Empirical significance levels were determined via gene-dropping simulations. A meta-analysis was performed by combining linkage results from the CAUC, OOA, AFRAM and ASHK samples and results were compared to previously-reported loci for myopia and refraction.
Results: Suggestive evidence of linkage was found at: 12q24 (LOD=4.583, P=0.00037) and 4q21 (LOD=2.72, P=0.0028) in the CAUC sample; and at 5qter (LOD=3.271, P=0.0014) in the OOA. Meta-analysis linkage results were largely driven by population-specific signals from ASHK and AFRAM families. The meta-analysis showed suggestive evidence of linkage to 4q21-22 (meta-P=0.00214) adjacent to the previously-reported MYP9 and MYP11 loci.
Conclusions: We found suggestive evidence of linkage of ocular refraction to 12q24 and 4q21 in Caucasian, and to 5qter in Amish families. Our meta-analysis supports the view that several genes play a role in refractive development across populations. In MFS families, four broad genomic regions (on 1p, 4q, 7p and 12q) most likely contain genes that influence ocular refraction.
Key Words:
myopia, linkage analysis, refraction, meta-analysis, genomewide scan
