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1.  Dissecting the genetic heterogeneity of myopia susceptibility in an Ashkenazi Jewish population using ordered subset analysis 
Molecular Vision  2011;17:1641-1651.
Despite many years of research, most of the genetic factors contributing to myopia development remain unknown. Genetic studies have pointed to a strong inherited component, but although many candidate regions have been implicated, few genes have been positively identified.
We have previously reported 2 genomewide linkage scans in a population of 63 highly aggregated Ashkenazi Jewish families that identified a locus on chromosome 22. Here we used ordered subset analysis (OSA), conditioned on non-parametric linkage to chromosome 22 to detect other chromosomal regions which had evidence of linkage to myopia in subsets of the families, but not the overall sample.
Strong evidence of linkage to a 19-cM linkage interval with a peak OSA nonparametric allele-sharing logarithm-of-odds (LOD) score of 3.14 on 20p12-q11.1 (ΔLOD=2.39, empirical p=0.029) was identified in a subset of 20 families that also exhibited strong evidence of linkage to chromosome 22. One other locus also presented with suggestive LOD scores >2.0 on chromosome 11p14-q14 and one locus on chromosome 6q22-q24 had an OSA LOD score=1.76 (ΔLOD=1.65, empirical p=0.02).
The chromosome 6 and 20 loci are entirely novel and appear linked in a subset of families whose myopia is known to be linked to chromosome 22. The chromosome 11 locus overlaps with the known Myopia-7 (MYP7, OMIM 609256) locus. Using ordered subset analysis allows us to find additional loci linked to myopia in subsets of families, and underlines the complex genetic heterogeneity of myopia even in highly aggregated families and genetically isolated populations such as the Ashkenazi Jews.
PMCID: PMC3123157  PMID: 21738393
2.  Genetic linkage study of high-grade myopia in a Hutterite population from South Dakota 
Molecular Vision  2007;13:229-236.
Myopia is a common, complex disorder, and severe forms have implications for blindness due to increased risk of premature cataracts, glaucoma, retinal detachment, and macular degeneration. Autosomal dominant (AD) non-syndromic high-grade myopia has been mapped to chromosomes 18p11.31, 12q21-23, 17q21-23, 7q36, 2q37.1, 7p15.3, 15q12-13, 3q26, 4q12, 8p23, 4q22-q27, 1p36, and Xq23-q25. Here, we demonstrate evidence of linkage for AD non-syndromic high-grade myopia in a large Hutterite family to a locus on chromosome 10q21.1.
After clinical evaluation, genomic DNA was genotyped from 29 members of a Hutterite family from South Dakota (7 affected). The average refractive error of affected individuals was -7.04 diopters. Microsatellite markers were used to exclude linkage to the known AD nonsyndromic high-grade myopia loci as well as to syndromic high-grade myopia loci. A genome screen was then performed using 382 markers with an average inter-marker distance of 10 cM followed by fine-point mapping in all regions of the genome that gave positive LOD scores. SimWalk2 software was used for multipoint linkage based on AD and autosomal recessive (AR) models with a penetrance of 90% and a disease allele frequency of 0.001.
A maximum multipoint LOD score of 3.22 was achieved under an AD model at microsatellite marker D10S1643. Fine point mapping and haplotype analysis defined a critical region of 2.67 cM on chromosome 10q21.1. Haplotype analysis demonstrated two distinct haplotypes segregating with high-grade myopia, indicative of two distinct mutations occurring in the same gene.
We have identified a presumptive myopia locus for high-grade myopia based on linkage and haplotype analysis.
PMCID: PMC2633468  PMID: 17327828
3.  Genomewide Linkage Scans for Ocular Refraction and Meta-analysis of Four Populations in the Myopia Family Study 
Genomewide linkage scans were performed 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.
Two hundred seventy-one CAUC and 411 OOA participants (36 and 61 families, respectively) were recruited 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 by 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.
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.
The results showed suggestive evidence of linkage of ocular refraction to 12q24 and 4q21 in CAUC and to 5qter in OOA families. The 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.
PMCID: PMC2885973  PMID: 19151385
4.  Association of Matrix Metalloproteinase Gene Polymorphisms with Refractive Error in Amish and Ashkenazi Families 
The role of polymorphisms in matrix metalloproteinase genes with variations in refractive error among Orthodox Ashkenazi Jewish and Old Order Amish families was investigated. The results showed statistically significant genetic associations of refraction with two markers in MMP regions in the Amish population, but not among the Ashkenazim.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in scleral extracellular matrix remodeling and have shown differential expression in experimental myopia. The genetic association of refractive error and polymorphisms in MMP and TIMP genes in Old Order Amish (AMISH) and Ashkenazi Jewish (ASHK) families was investigated.
Individuals from 55 AMISH and 63 ASHK families participated in the study. Ascertainment was designed to enrich the families for myopia; the mean spherical equivalent (MSE) refractive error (SD) was −1.61 (2.72) D in the AMISH, and −3.56 (3.32) D in the ASHK. One hundred forty-six common haplotype tagging SNPs covering 14 MMP and 4 TIMP genes were genotyped in 358 AMISH and 535 ASHK participants. Association analyses of MSE and the spherical component of refraction (SPH) were performed separately for the AMISH and the ASHK. Bonferroni-corrected significance thresholds and local false discovery rates were used to account for multiple testing.
After they were filtered for quality-control, 127 SNPs were included in the analyses. No polymorphisms showed statistically significant association to refraction in the ASHK (minimum P = 0.0132). In AMISH, two SNPs showed evidence of association with refractive phenotypes: rs1939008 (P = 0.00016 for SPH); and rs9928731 (P = 0.00026 for SPH). These markers were each estimated to explain <5% of the variance of SPH in the AMISH sample.
Statistically significant genetic associations of ocular refraction to polymorphisms near MMP1 and within MMP2 were identified in the AMISH but not among the ASHK families. The results suggest that the MMP1 and MMP2 genes are involved in refractive variation in the AMISH. Genetic and/or environmental heterogeneity most likely contribute to differences in association results between ethnic groups.
PMCID: PMC3066601  PMID: 20484597
5.  Genome-wide Scan of African-American and White Families for Linkage to Myopia 
American journal of ophthalmology  2008;147(3):512-517.e2.
To identify myopia susceptibility genes influencing common myopia in 94 African-American and 36 White families.
A prospective study of families with myopia consisting of a minimum of two individuals affected with myopia.
Extended families consisting of at least two siblings affected with myopia were ascertained. A genome-wide linkage scan using 387 markers was conducted by the Center for Inherited Disease Research. Linkage analyses were conducted with parametric and nonparametric methods. Model-free linkage analysis was performed maximizing over penetrance and over dominance (that is, fitting a wide range of both dominant and recessive models).
Under the model-free analysis, the maximum two point heterogeneity logarithm of the odds score (MALOD) was 2.87 at D6S1009 in the White cohort and the maximum multipoint MALOD was 2.42 at D12S373-D12S1042 in the same cohort. The nonpara-metric linkage (NPL) maximum multipoint at D6S1035 had a P value of .005. An overall multipoint NPL score was obtained by combining NPL scores from both populations. The highest combined NPL score was observed at D20S478 with a significant P value of .008. Suggestive evidence of linkage in the White cohort mapped to a previously mapped locus on chromosome 11 at D11S1981 (NPL = 2.14; P = .02).
Suggestive evidence of linkage to myopia in both African Americans and Whites was seen on chromosome 20 and became more significant when the scores were combined for both groups. The locus on chromosome 11 independently confirms a report by Hammond and associates mapping a myopia quantitative trait locus to this region.
PMCID: PMC4152232  PMID: 19026404
6.  Candidate gene and locus analysis of myopia 
Molecular Vision  2007;13:1012-1019.
A previous study has reported evidence of a strong linkage, but no association, between paired box gene 6 (PAX6) and myopia. We attempted to replicate these findings and to conduct a candidate gene and locus evaluation of genetic involvement in common forms of myopia.
Samples were collected from 517 individuals in 123 families with a myopic child participating in the Orinda Longitudinal Study of Myopia or the Contact Lens and Myopia Progression Study. Myopia in the proband children was defined as -0.75 D or more and as being present in both meridians on cycloplegic autorefraction (1% tropicamide). Affected status in parents and siblings was determined by survey. After DNA was extracted from buccal mucosal cells and genotyped using assays for microsatellite markers and single nucleotide polymorphisms (SNPs), DNA was analyzed for linkage disequilibrium. Markers on chromosomes 12 and 18 were selected as regions previously associated with pathological myopia. SNPs were also analyzed in genes where their expression pattern or their association with syndromes conveys myopia as part of the phenotype (FGF2, BDNF, COL2A1, COL18A1, and PAX6).
The SNP rs1635529 for COL2A1 on 12q13.11 showed highly significant over-transmission to affected individuals (p=0.00007). No SNP for FGF2, BDNF, COL18A1, or PAX6 showed significant over-transmission to affected individuals after correction for multiple comparisons. Markers on chromosome 12 and 18 previously associated with pathological myopia also showed no significant associations with the more common form of myopia in this study.
As reported previously by others, PAX6 showed no association with myopia. Associations in the current analysis are suggestive of involvement of COL2A1. Future studies should focus on replication in other samples and in genome-wide approaches.
PMCID: PMC2776540  PMID: 17653045
7.  Linkage analysis of high myopia susceptibility locus in 26 families 
Molecular Vision  2008;14:2566-2574.
We conducted a linkage analysis in high myopia families to replicate suggestive results from chromosome 7q36 using a model of autosomal dominant inheritance and genetic heterogeneity. We also performed a genome-wide scan to identify novel loci.
Twenty-six families, with at least two high-myopic subjects (ie. refractive value in the less affected eye of −5 diopters) in each family, were included. Phenotypic examination included standard autorefractometry, ultrasonographic eye length measurement, and clinical confirmation of the non-syndromic character of the refractive disorder. Nine families were collected de novo including 136 available members of whom 34 were highly myopic subjects. Twenty new subjects were added in 5 of the 17 remaining families. A total of 233 subjects were submitted to a genome scan using ABI linkage mapping set LMSv2-MD-10, additional markers in all regions where preliminary LOD scores were greater than 1.5 were used. Multipoint parametric and non-parametric analyses were conducted with the software packages Genehunter 2.0 and Merlin 1.0.1. Two autosomal recessive, two autosomal dominant, and four autosomal additive models were used in the parametric linkage analyses.
No linkage was found using the subset of nine newly collected families. Study of the entire population of 26 families with a parametric model did not yield a significant LOD score (>3), even for the previously suggestive locus on 7q36. A non-parametric model demonstrated significant linkage to chromosome 7p15 in the entire population (Z-NPL=4.07, p=0.00002). The interval is 7.81 centiMorgans (cM) between markers D7S2458 and D7S2515.
The significant interval reported here needs confirmation in other cohorts. Among possible susceptibility genes in the interval, certain candidates are likely to be involved in eye growth and development.
PMCID: PMC2613077  PMID: 19122830
8.  An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia 
Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite markers and a limited number of pedigrees. In this study, whole-genome linkage scans were performed for high-grade myopia, using single nucleotide polymorphisms (SNPs) in 254 families from five independent sites.
Genomic DNA samples from 1411 subjects were genotyped (Linkage Panel IVb; Illumina, San Diego, CA). Linkage analyses were performed on 1201 samples from 10 Asian, 12 African-American, and 221 Caucasian families, screening for 5744 SNPs after quality-control exclusions. Two disease states defined by sphere (SPH) and spherical equivalence (SE; sphere+cylinder/2) were analyzed. Parametric and nonparametric two-point and multipoint linkage analyses were performed using the FASTLINK, HOMOG, and MERLIN programs. Multiple stratified datasets were examined, including overall, center-specific, and race-specific. Linkage regions were declared suggestive if they had a peak LOD score ≥ 1.5.
The MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated. The novel region q34.11 on chromosome 9 (max NPL= 2.07 at rs913275) was identified. Chromosome 12, region q21.2-24.12 (36.59 cM, MYP3 locus) showed significant linkage (peak HLOD = 3.48) at rs337663 in the overall dataset by SPH and was detected by the Duke, Asian, and Caucasian subsets as well. Potential shared interval was race dependent—a 9.4-cM region (rs163016–rs1520724) driven by the Asian subset and a 1343-cM region (rs163016–rs1520724) driven by the Caucasian subset.
The present study is the largest linkage scan to date for familial high-grade myopia. The outcomes will facilitate the identification of genes implicated in myopic refractive error development and ocular growth.
PMCID: PMC3696634  PMID: 19324860
9.  Refinement of the X-linked Nonsyndromic High-Grade Myopia Locus MYP1 on Xq28 and Exclusion of 13 Known Positional Candidate Genes by Direct Sequencing 
Myopia affects more people worldwide than any other chronic condition, and it is increasing in all populations across the globe. It affects ∼25% of the U.S. general population between the ages of 12 and 54 years. The present study is a genetic investigation of X-linked high-grade myopia that maps to Xq28.
Myopia is a common vision problem affecting almost one third of the world's population. It can occur as an isolated genetic condition or be associated with other anomalies and/or syndromes. Seventeen myopia loci have been identified on various chromosomes; however, no specific gene mutations have yet been identified.
Two large multigeneration Asian Indian pedigrees (UR006 and UR077) with isolated, nonsyndromic myopia were studied, in which the condition appeared to segregate as an X-linked recessive trait (MYP1; MIM 310460). The degree of myopia was variable in both families, ranging from −6 to −23 D (mean, –8.48 D) with the majority >7.0 D. To map the myopia locus in these families, polymorphic microsatellite markers covering the entire X chromosome were used in linkage analyses performed on 42 genomic DNA samples (13 affected and 29 normal) from both families.
Marker DXYS154, which is located within the pseudoautosomal region in distal Xq28 (PAR2; pseudoautosomal region 2), gave a combined maximum LOD score of 5.3 at θ = 0 under an autosomal recessive model. Other markers in the region (near but not within the PAR2 region) that showed no recombination with the phenotype in both the families included DXS1108, DXS8087, and F8i13.
Observation of recombination in family UR006 refined the disease locus to a ∼1.25-Mb region flanked by the proximal marker DXS1073 and distal marker DXYS154. Mutation search in exons and splice junctions of candidate genes CTAG2, GAB3, MPP1, F8Bver, FUNDC2, VBP1, RAB39B, CLIC2, TMLHE, SYBL, IL9R, SPRY3, and CXYorf1 did not detect a pathogenic or predisposing variant.
PMCID: PMC3176007  PMID: 21357393
10.  An international collaborative family-based whole genome quantitative trait linkage scan for myopic refractive error 
Molecular Vision  2012;18:720-729.
To investigate quantitative trait loci linked to refractive error, we performed a genome-wide quantitative trait linkage analysis using single nucleotide polymorphism markers and family data from five international sites.
Genomic DNA samples from 254 families were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel IVb. Quantitative trait linkage analysis was performed on 225 Caucasian families and 4,656 markers after accounting for linkage disequilibrium and quality control exclusions. Two refractive quantitative phenotypes, sphere (SPH) and spherical equivalent (SE), were analyzed. The SOLAR program was used to estimate identity by descent probabilities and to conduct two-point and multipoint quantitative trait linkage analyses.
We found 29 markers and 11 linkage regions reaching peak two-point and multipoint logarithms of the odds (LODs)>1.5. Four linkage regions revealed at least one LOD score greater than 2: chromosome 6q13–6q16.1 (LOD=1.96 for SPH, 2.18 for SE), chromosome 5q35.1–35.2 (LOD=2.05 for SPH, 1.80 for SE), chromosome 7q11.23–7q21.2 (LOD=1.19 for SPH, 2.03 for SE), and chromosome 3q29 (LOD=1.07 for SPH, 2.05 for SE). Among these, the chromosome 6 and chromosome 5 regions showed the most consistent results between SPH and SEM. Four linkage regions with multipoint scores above 1.5 are near or within the known myopia (MYP) loci of MYP3, MYP12, MYP14, and MYP16. Overall, we observed consistent linkage signals across the SPH and SEM phenotypes, although scores were generally higher for the SEM phenotype.
Our quantitative trait linkage analyses of a large myopia family cohort provided additional evidence for several known MYP loci, and identified two additional potential loci at chromosome 6q13–16.1 and chromosome 5q35.1–35.2 for myopia. These results will benefit the efforts toward determining genes for myopic refractive error.
PMCID: PMC3324362  PMID: 22509102
11.  Fine-mapping of candidate region in Amish and Ashkenazi families confirms linkage of refractive error to a QTL on 1p34-p36 
Molecular Vision  2009;15:1398-1406.
A previous genome-wide study in Orthodox Ashkenazi Jewish pedigrees showed significant linkage of ocular refraction to a Quantitative Trait Locus (QTL) on 1p34-36.1. We carried out a fine-mapping study of this region in Orthodox Ashkenazi Jewish (ASHK) and Old Order Amish (OOA) families to confirm linkage and narrow the candidate region.
Families were recruited from ASHK and OOA American communities. The samples included: 402 individuals in 53 OOA families; and 596 members in 68 ASHK families. Families were ascertained to contain multiple myopic individuals. Genotyping of 1,367 SNPs was carried out within a 35cM (~23.9 Mb) candidate QTL region on 1p34-36. Multipoint variance components (VC) and regression-based (REG) linkage analyses were carried out separately in OOA and ASHK groups, and in a combined analysis that included all families.
Evidence of linkage of refractive error was found in both OOA (VC LOD=3.45, REG LOD=3.38 at ~59 cM) and ASHK families (VC LOD=3.12, REG LOD=4.263 at ~66 cM). Combined analyses showed three highly significant linkage peaks, separated by ~11cM (or 10 Mb), within the candidate region.
In a fine-mapping linkage study of OOA and ASHK families, we have confirmed linkage of refractive error to a QTL on 1p. The area of linkage has been narrowed down to a gene-rich region at 1p34.2-35.1 containing ~124 genes.
PMCID: PMC2713730  PMID: 19626131
12.  Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families 
A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers.
GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene.
The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer.
Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
PMCID: PMC2949638  PMID: 20637093
13.  Identification of a locus for autosomal dominant high myopia on chromosome 5p13.3-p15.1 in a Chinese family 
Molecular Vision  2010;16:2043-2054.
Myopia and its extreme form, high myopia, are common vision disorders worldwide, especially in Asia. Identifying genetic markers is a useful step toward understanding the genetic basis of high myopia, particularly in the Chinese population, where it is highly prevalent. This study was conducted to provide evidence of linkage for autosomal dominant high myopia to a locus on chromosome 5p13.3-p15.1 in a large Chinese family.
After clinical evaluation, genomic DNA from 29 members of this family was genotyped. A genome-wide screen was then performed using 382 markers with an average inter-marker distance of 10 cM, and two-point linkage was analyzed using the MLINK program. Mutation analysis of the candidate genes was performed using direct sequencing.
Linkage to the known autosomal dominant high myopia loci was excluded. The genome-wide screening identified a maximum two-point LOD score of 3.71 at θ=0.00 with the microsatellite marker D5S502. Fine mapping and haplotype analysis defined a critical region of 11.69 cM between D5S2096 and D5S1986 on chromosome 5p13.3-p15.1. Sequence analysis of the candidate genes inside the linked region did not identify any causative mutations.
A genetic locus was mapped to chromosome 5p13.3-p15.1 in a large Chinese family with autosomal dominant high myopia.
PMCID: PMC2965568  PMID: 21042559
14.  Novel locus for X linked recessive high myopia maps to Xq23–q25 but outside MYP1 
Journal of Medical Genetics  2006;43(5):e20.
High myopia is a common genetic variation in most cases, affecting 1–2% of people, and is the fourth most common disorder causing blindness worldwide. Six autosomal dominant loci and one X‐linked recessive locus have been reported, but no genes responsible for high myopia have been identified.
To report a Chinese family in which six males presented with high myopia consistent with an X linked recessive trait.
Affected individuals shared three common features: high myopia, reduced visual acuity, and fundal changes of high myopia. Protan and deutan were observed in the family, but they did not co‐segregate with the high myopia phenotype. X‐chromosome‐wide linkage analysis mapped the high myopia locus to a 25 cM (14.9 Mb) region on Xq23–q25 between DXS1210 and DXS8057, with maximum two point lod scores at θ = 0 of 2.75 and 2.29 for DXS1001 and DXS8059, respectively.
This new myopia locus is outside the linked region of the first high myopia locus (MYP1). Refinement of the linkage region with additional families and screening candidate genes for mutation may lead to the identification of the defect gene.
PMCID: PMC2564525  PMID: 16648373
X linked recessive high myopia; linkage; cone dysfunction; MYP1
15.  Clinical and linkage study on a consanguineous Chinese family with autosomal recessive high myopia 
Molecular Vision  2009;15:312-318.
A linkage study on autosomal recessive high myopia (arHM) has not been reported, although several loci for autosomal dominant high myopia (adHM) have been mapped. Data from a consanguineous Chinese family with arHM were collected to map the genetic locus associated with this condition.
Phenotypic information and DNA samples were collected from family members. A genome-wide linkage scan combined with homozygosity mapping was performed by using 382 microsatellite DNA markers from the entire genome spaced at intervals of about 10 cM.
The pedigree and clinical data of the family indicate that the high myopia is autosomal recessive. A genome-wide scan of chromosomes 1–22 gave a LOD score greater than 1.0 for 22 markers. Linkage to most of these markers was not supported by closely flanking markers except for three possible loci on chromosomes 11, 14, and 17. Fine mapping and haplotype analysis provide evidence for a locus at 14q22.1-q24.2 in a 25.23 Mb region between markers D14S984 and D14S999 with a maximum LOD score of 2.19. All 11 microsatellite markers inside the linkage interval as well as haplotype construction point to a gene at this locus. Linkage elsewhere on chromosome 11 and chromosome 17 could not be excluded due to the small size of the family.
Pedigree and clinical data suggest that an autosomal recessive gene is responsible for high myopia in a consanguineous Chinese family. Genome-wide linkage analysis was used to map the gene for high myopia to a few limited loci. The resultant information should help future studies identify the gene for arHM. To our knowledge, this report is the first clinical and linkage study on a consanguineous family with arHM.
PMCID: PMC2635848  PMID: 19204786
16.  A Genome-Wide Association Analysis Identified a Novel Susceptible Locus for Pathological Myopia at 11q24.1 
PLoS Genetics  2009;5(9):e1000660.
Myopia is one of the most common ocular disorders worldwide. Pathological myopia, also called high myopia, comprises 1% to 5% of the general population and is one of the leading causes of legal blindness in developed countries. To identify genetic determinants associated with pathological myopia in Japanese, we conducted a genome-wide association study, analyzing 411,777 SNPs with 830 cases and 1,911 general population controls in a two-stage design (297 cases and 934 controls in the first stage and 533 cases and 977 controls in the second stage). We selected 22 SNPs that showed P-values smaller than 10−4 in the first stage and tested them for association in the second stage. The meta-analysis combining the first and second stages identified an SNP, rs577948, at chromosome 11q24.1, which was associated with the disease (P = 2.22×10−7 and OR of 1.37 with 95% confidence interval: 1.21–1.54). Two genes, BLID and LOC399959, were identified within a 200-kb DNA encompassing rs577948. RT–PCR analysis demonstrated that both genes were expressed in human retinal tissue. Our results strongly suggest that the region at 11q24.1 is a novel susceptibility locus for pathological myopia in Japanese.
Author Summary
Myopia is one of the most common ocular disorders with elongation of axis of the eyeball. Pathological myopia or high myopia, a subset of myopia which is characterized with excessive axial elongation and degenerative changes of the eye, is a leading cause of visual impairment. Since genetic factors play significant roles in its development, identification of genetic determinants is an urgent and important issue. Although family-based linkage analyses have isolated at least 16 susceptible chromosomal loci for pathological or common myopia, no gene responsible for the disease has been identified. We conducted the first genome-wide case/control association study of pathological myopia in a two-stage design using 411,777 markers with 830 Japanese patients and 1,911 Japanese controls. We identified a region strongly suggestive for the disease susceptibility at chromosome 11q24.1 containing BLID and LOC399959. Their expression was confirmed in human retina with RT–PCR. BLID encodes an inducer of apoptotic cell death, and apoptosis is known to play an important functional role in pathological myopia. We believe that our study contributes to further dissect the molecular events underlying the development and progression of pathological myopia.
PMCID: PMC2735651  PMID: 19779542
17.  Hepatocyte growth factor and myopia: Genetic association analyses in a caucasian population 
Molecular Vision  2009;15:1028-1035.
Hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (C-MET) genes have previously been reported to be associated with myopia in Asian family-based and case-control association studies, respectively. We examined whether these genes were associated with myopia in a Caucasian family dataset biased towards high myopia.
Participating families had at least one offspring with high myopia (≤-5.00 diopters [D]). Genotyping was performed with tagging single nucleotide polymorphisms (SNPs) for each candidate gene using Taqman™ allelic discrimination assays. The data were analyzed with two family-based association methods, the pedigree disequilibrium test (PDT) and the association in the presence of linkage (APL) test. Analyses compared 1) high myopia (<-5.00 D), 2) mild to moderate myopia (-0.50 to -5.00 D), 3) any myopia (<-0.50 D) and 4) extreme high myopia (≤-10.00 D) versus emmetropia using refractive error as either sphere (SPH) or spherical equivalent (SE=sphere + [cylinder/2]). Bonferroni correction was applied to adjust for multiple testing leading to significance levels of 0.0125 for HGF and 0.008 for C-MET. Two and three-marker sliding window haplotype association tests using APL were also performed for HGF markers. Significance levels for haplotype association testing were set at 0.01 for the global tests, and 0.007 for the three marker haplotype specific tests and 0.0125 for the two marker haplotype specific tests.
A total of 146 multiplex families consisting of 649 Caucasian subjects were included. The HGF SNP, rs3735520 (APL p=0.002768 for SPH and 0.005609 for SE), and the haplotypes, rs2286194-rs3735520-rs17501108 (APL p=0.007403 for SPH and 0.062685 for SE) and rs12536657-rs2286194 (APL p=0.004219 for SPH and 0.00518 for SE), showed significant association with mild to moderate myopia versus emmetropia. A promising association between extreme high myopia and the HGF SNP, rs2286194, was also found (APL p=0.005763 for SPH and 0.004103 for SE). No evidence of association was found in the SNPs tested for C-MET.
This study supports a strong association between the mild to moderate myopia group and the HGF SNP rs3735520 and the HGF haplotypes rs2286194-rs3735520-rs17501108 and rs12536657-rs2286194, and a moderate association of the extreme high myopia with rs2286194. C-MET polymorphism statistical associations with myopia in an Asian study were not replicated in our Caucasian cohort. HGF may be a potential myopia candidate gene for further investigation.
PMCID: PMC2684748  PMID: 19471602
18.  Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate 
PLoS Genetics  2014;10(3):e1004229.
Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.
Author Summary
Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable efforts genetic studies have yet to reveal the precise genetic underpinnings of the disorder. In this study we have analyzed a large extended pedigree of Old Order Amish that segregates bipolar disorder. Our study design integrates both dense genotype and whole-genome sequence data. In a combined linkage and association analysis we identify five chromosomal regions with nominally significant or suggestive evidence for linkage, several of which constitute replication of earlier linkage findings for bipolar disorder in non-Amish families. Association analysis of genetic variants in each of the linkage regions yielded a number of plausible candidate genes for bipolar disorder. The striking genetic heterogeneity we observed in this genetic isolate has profound implications for the study of bipolar disorder in the general population.
PMCID: PMC3953017  PMID: 24625924
19.  Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates 
Autism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors. Twin and family studies point to a significant genetic etiology, and several groups have performed genomic linkage screens to identify susceptibility loci.
We performed a genome-wide linkage screen in 158 combined Tufts, Vanderbilt and AGRE (Autism Genetics Research Exchange) multiplex autism families using parametric and nonparametric methods with a categorical autism diagnosis to identify loci of main effect. Hypothesizing interdependence of genetic risk factors prompted us to perform exploratory studies applying the Ordered-Subset Analysis (OSA) approach using LOD scores as the trait covariate for ranking families. We employed OSA to test for interlocus correlations between loci with LOD scores ≥1.5, and empirically determined significance of linkage in optimal OSA subsets using permutation testing. Exploring phenotypic correlates as the basis for linkage increases involved comparison of mean scores for quantitative trait-based subsets of autism between optimal subsets and the remaining families.
A genome-wide screen for autism loci identified the best evidence for linkage to 17q11.2 and 19p13, with maximum multipoint heterogeneity LOD scores of 2.9 and 2.6, respectively. Suggestive linkage (LOD scores ≥1.5) at other loci included 3p, 6q, 7q, 12p, and 16p. OSA revealed positive correlations of linkage between the 19p locus and 17q, between 19p and 6q, and between 7q and 5p. While potential phenotypic correlates for these findings were not identified for the chromosome 7/5 combination, differences indicating more rapid achievement of "developmental milestones" was apparent in the chromosome 19 OSA-defined subsets for 17q and 6q. OSA was used to test the hypothesis that 19p linkage involved more rapid achievement of these milestones and it revealed significantly increased LOD* scores at 19p13.
Our results further support 19p13 as harboring an autism susceptibility locus, confirm other linkage findings at 17q11.2, and demonstrate the need to analyze more discreet trait-based subsets of complex phenotypes to improve ability to detect genetic effects.
PMCID: PMC546213  PMID: 15647115
20.  The Genetics of Reading Disability in an Often Excluded Sample: Novel Loci Suggested for Reading Disability in Rolandic Epilepsy 
PLoS ONE  2012;7(7):e40696.
Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating “pure” dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub-phenotypes of RE.
We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus.
In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French-Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD  = 1.81), possibly because the replication sample did not have French Canadian representation.
Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in “pure” dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci.
PMCID: PMC3399896  PMID: 22815793
21.  A linkage study of candidate loci in familial Parkinson's Disease 
BMC Neurology  2003;3:6.
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Most cases are sporadic, however familial cases do exist. We examined 12 families with familial Parkinson's disease ascertained at the Movement Disorder clinic at the Oregon Health Sciences University for genetic linkage to a number of candidate loci. These loci have been implicated in familial Parkinson's disease or in syndromes with a clinical presentation that overlaps with parkinsonism, as well as potentially in the pathogenesis of the disease.
The examined loci were PARK3, Parkin, DRD (dopa-responsive dystonia), FET1 (familial essential tremor), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), Ret, DAT1 (the dopamine transporter), Nurr1 and Synphilin-1. Linkage to the α-synuclein gene and the Frontotemporal dementia with parkinsonism locus on chromosome 17 had previously been excluded in the families included in this study. Using Fastlink, Genehunter and Simwalk both parametric and model-free non-parametric linkage analyses were performed.
In the multipoint parametric linkage analysis lod scores were below -2 for all loci except FET1 and Synphilin-1 under an autosomal dominant model with incomplete penetrance. Using non-parametric linkage analysis there was no evidence for linkage, although linkage could not be excluded. A few families showed positive parametric and non-parametric lod scores indicating possible genetic heterogeneity between families, although these scores did not reach any degree of statistical significance.
We conclude that in these families there was no evidence for linkage to any of the loci tested, although we were unable to exclude linkage with both parametric and non-parametric methods.
PMCID: PMC184377  PMID: 12882651
22.  Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia 
PLoS Genetics  2012;8(6):e1002753.
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = −0.16 mm per minor allele, Pmeta = 2.69×10−10). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) = 0.75, 95% CI: 0.68–0.84, Pmeta = 4.38×10−7) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.
Author Summary
Myopic individuals exhibit an increase in ocular axial length (AL). As a highly heritable ocular biometry of refractive error, identification of quantitative trait loci influencing AL variation would be valuable in informing the biological etiology of myopia. We have determined that a genetic locus on chromosome 1q41 containing zinc-finger pseudogene ZC3H11B is associated with AL and high myopia through a meta-analysis of three genome-wide association scans on AL in Chinese and Malays, with validation for high myopia association in two additional Japanese cohorts. In addition, variations in the expression of murine gene ZC3H11A and two neighboring genes SLC30A10 and LYPLAL1 in the retina and sclera in a myopic mouse model implicate the role of these genes in myopia onset. To our knowledge, this is the first genome-wide survey of single nucleotide polymorphism (SNP) variation of AL in Asians. Our results suggest that genetic variants at chromosome 1q41 have potential roles in both common and high myopia.
PMCID: PMC3369958  PMID: 22685421
23.  Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q 
BMC Cancer  2008;8:87.
Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer.
Statistical analysis was performed using multipoint parametric and nonparametric linkage.
Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1).
The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.
PMCID: PMC2324103  PMID: 18380902
24.  Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms 
Molecular psychiatry  2009;14(8):786-795.
A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1,615 affected and 1,602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5,861 single nucleotide polymorphisms (SNPs; Illumina 4.0 linkage map). Suggestive evidence for linkage (European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in non-parametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-lod support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region.
PMCID: PMC2714870  PMID: 19223858
Genome; Human; Genotype; Humans; Schizophrenia/*genetics; Genetic Predisposition to Disease; *Linkage (Genetics)
25.  Association Mapping of the High-Grade Myopia MYP3 Locus Reveals Novel Candidates UHRF1BP1L, PTPRR, and PPFIA2 
Myopia, or nearsightedness, is a common ocular genetic disease for which over 20 candidate genomic loci have been identified. The high-grade myopia locus, MYP3, has been reported on chromosome 12q21–23 by four independent linkage studies.
We performed a genetic association study of the MYP3 locus in a family-based high-grade myopia cohort (n = 82) by genotyping 768 single-nucleotide polymorphisms (SNPs) within the linkage region. Qualitative testing for high-grade myopia (sphere ≤ −5 D affected, > −0.5 D unaffected) and quantitative testing on the average dioptric sphere were performed.
Several genetic markers were nominally significantly associated with high-grade myopia in qualitative testing, including rs3803036, a missense mutation in PTPRR (P = 9.1 × 10−4) and rs4764971, an intronic SNP in UHRF1BP1L (P = 6.1 × 10−4). Quantitative testing determined statistically significant SNPs rs4764971, also found by qualitative testing (P = 3.1 × 10−6); rs7134216, in the 3′ untranslated region (UTR) of DEPDC4 (P = 5.4 × 10−7); and rs17306116, an intronic SNP within PPFIA2 (P < 9 × 10−4). Independently conducted whole genome expression array analyses identified protein tyrosine phosphatase genes PTPRR and PPFIA2, which are in the same gene family, as differentially expressed in normal rapidly growing fetal relative to normal adult ocular tissue (confirmed by RT-qPCR).
In an independent high-grade myopia cohort, an intronic SNP in UHRF1BP1L, rs4764971, was validated for quantitative association, and SNPs within PTPRR (quantitative) and PPFIA2 (qualitative and quantitative) approached significance. Three genes identified by our association study and supported by ocular expression and/or replication, UHRF1BP1L, PTPRR, and PPFIA2, are novel candidates for myopic development within the MYP3 locus that should be further studied.
Association mapping of the MYP3 locus reveals novel candidate genes.
PMCID: PMC3621505  PMID: 23422819

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