Identification and replication of three novel myopia common susceptibility gene loci on chromosome 3q26 using linkage and linkage disequilibrium mapping

TY - JOUR

T1 - Identification and replication of three novel myopia common susceptibility gene loci on chromosome 3q26 using linkage and linkage disequilibrium mapping

AU - Andrew, Toby

AU - Maniatis, Nikolas

AU - Carbonaro, Francis

AU - Liew, S H Melissa

AU - Lau, Winston

AU - Spector, Tim D

AU - Hammond, Christopher J

PY - 2008/10

Y1 - 2008/10

N2 - Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505-180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533-182,688 kb) and PSARL (184,386 kb; 95% CI 184,356-184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p <10(-7), p <10(-10), and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial- led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia.

AB - Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505-180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533-182,688 kb) and PSARL (184,386 kb; 95% CI 184,356-184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p <10(-7), p <10(-10), and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial- led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia.

KW - Polymorphism, Single Nucleotide

KW - Membrane Transport Proteins

KW - Mitochondrial Membrane Transport Proteins

KW - Humans

KW - Aged

KW - Chromosome Mapping

KW - Linkage Disequilibrium

KW - Chromosomes, Human, Pair 3

KW - Transcription Factors

KW - Aged, 80 and over

KW - Adult

KW - Mitochondrial Proteins

KW - Genetic Predisposition to Disease

KW - Adolescent

KW - HMGB Proteins

KW - Male

KW - DNA-Binding Proteins

KW - Diseases in Twins

KW - Myopia

KW - SOXB1 Transcription Factors

KW - Case-Control Studies

KW - GTP Phosphohydrolases

KW - Middle Aged

KW - Female

KW - Presenilins

U2 - 10.1371/journal.pgen.1000220

DO - 10.1371/journal.pgen.1000220

M3 - Article

C2 - 18846214

SN - 1553-7404

VL - 4

JO - PL o S Genetics

JF - PL o S Genetics

IS - 10

M1 - e1000220

ER -