Limits...
Fine-mapping of candidate region in Amish and Ashkenazi families confirms linkage of refractive error to a QTL on 1p34-p36.

Wojciechowski R, Bailey-Wilson JE, Stambolian D - Mol. Vis. (2009)

Bottom Line: 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.Combined analyses showed three highly significant linkage peaks, separated by approximately 11cM (or 10 Mb), within the candidate region.The area of linkage has been narrowed down to a gene-rich region at 1p34.2-35.1 containing ~124 genes.

View Article: PubMed Central - PubMed

Affiliation: Inherited Disease Research Branch, National Human Genome Research Institute, 333 Cassell Drive, Baltimore, MD 21224, USA. robwoj@mail.nih.gov

ABSTRACT

Purpose: 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.

Methods: 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 (approximately 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.

Results: Evidence of linkage of refractive error was found in both OOA (VC LOD=3.45, REG LOD=3.38 at approximately 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 approximately 11cM (or 10 Mb), within the candidate region.

Conclusion: 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.

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Related in: MedlinePlus

Multipoint variance-components (left) and MERLIN-REGRESS (right) LOD scores for a combined analysis of OOA and ASHK families. Locations of local linkage peaks are indicated by vertical lines. Physical locations of SNP markers (bottom axis, in Mb) were determined using the NCBI dbSNP reference map, build 123. Genetic map positions (top axis, in cM) were obtained through the Rutgers Combined Linkage-Physical Map of the Human Genome. Because the relationship between physical position and genetic maps are non-linear, genetic positions in the figure are approximate.
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f2: Multipoint variance-components (left) and MERLIN-REGRESS (right) LOD scores for a combined analysis of OOA and ASHK families. Locations of local linkage peaks are indicated by vertical lines. Physical locations of SNP markers (bottom axis, in Mb) were determined using the NCBI dbSNP reference map, build 123. Genetic map positions (top axis, in cM) were obtained through the Rutgers Combined Linkage-Physical Map of the Human Genome. Because the relationship between physical position and genetic maps are non-linear, genetic positions in the figure are approximate.

Mentions: Results from multipoint VC and REG linkage analyses for ASHK and OOA families are presented in Figure 1. The maximum multipoint VC LOD scores for mean spherical equivalent refractive error were: 3.45 (p=0.00003) at ~59 cM (or 30.2 Mb) for OOA; and 3.12 (p=0.00007) at ~66.4 cM (or 34.6 Mb) for ASHK. For REG analyses, the maximum LOD scores were: 3.38 (p=0.00004) at ~59.7 cM (or 30.25 Mb) for OOA; and 4.263 (p<10-5) at ~66.4 cM (or 34.59 Mb) for ASHK families. The 1-LOD support intervals for VC and REG analyses of the OOA sample extend from rs212306 and rs9426315 at 1p35.3 (~59 cM), to rs471202 and rs6687223 at 1p35.2 (~60 cM); and the 1-LOD support regions in ASHK spanned from rs524787-rs549048 (1p35.1, ~65 cM) to rs704784 (1p34.2, 73 cM). The 2-LOD support intervals for VC analyses extended from 51.5 to 66.5 cM in the OOA, and between 53.9 and 62.7 cM for ASHK. Results from QTL multipoint linkage analyses after combining families from both populations are shown in Figure 2. Three linkage peaks were identified in the VC analysis: LOD= 4.99 at ~55 cM (24.3 Mb); LOD=5.04 at ~62 cM (31 Mb); and LOD=4.97 at ~66.5 cM (34.6 Mb). Three local linkage peaks were also found in the REG analyses: LOD=3.901 at ~54 cM (23.7 Mb); LOD=5.296 at ~60.6 cM (30.7 Mb); and LOD=5.054 at ~66 cM (34.3 Mb). All local linkage signals in the combined analysis were highly statistically significant (all p<10-5).


Fine-mapping of candidate region in Amish and Ashkenazi families confirms linkage of refractive error to a QTL on 1p34-p36.

Wojciechowski R, Bailey-Wilson JE, Stambolian D - Mol. Vis. (2009)

Multipoint variance-components (left) and MERLIN-REGRESS (right) LOD scores for a combined analysis of OOA and ASHK families. Locations of local linkage peaks are indicated by vertical lines. Physical locations of SNP markers (bottom axis, in Mb) were determined using the NCBI dbSNP reference map, build 123. Genetic map positions (top axis, in cM) were obtained through the Rutgers Combined Linkage-Physical Map of the Human Genome. Because the relationship between physical position and genetic maps are non-linear, genetic positions in the figure are approximate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713730&req=5

f2: Multipoint variance-components (left) and MERLIN-REGRESS (right) LOD scores for a combined analysis of OOA and ASHK families. Locations of local linkage peaks are indicated by vertical lines. Physical locations of SNP markers (bottom axis, in Mb) were determined using the NCBI dbSNP reference map, build 123. Genetic map positions (top axis, in cM) were obtained through the Rutgers Combined Linkage-Physical Map of the Human Genome. Because the relationship between physical position and genetic maps are non-linear, genetic positions in the figure are approximate.
Mentions: Results from multipoint VC and REG linkage analyses for ASHK and OOA families are presented in Figure 1. The maximum multipoint VC LOD scores for mean spherical equivalent refractive error were: 3.45 (p=0.00003) at ~59 cM (or 30.2 Mb) for OOA; and 3.12 (p=0.00007) at ~66.4 cM (or 34.6 Mb) for ASHK. For REG analyses, the maximum LOD scores were: 3.38 (p=0.00004) at ~59.7 cM (or 30.25 Mb) for OOA; and 4.263 (p<10-5) at ~66.4 cM (or 34.59 Mb) for ASHK families. The 1-LOD support intervals for VC and REG analyses of the OOA sample extend from rs212306 and rs9426315 at 1p35.3 (~59 cM), to rs471202 and rs6687223 at 1p35.2 (~60 cM); and the 1-LOD support regions in ASHK spanned from rs524787-rs549048 (1p35.1, ~65 cM) to rs704784 (1p34.2, 73 cM). The 2-LOD support intervals for VC analyses extended from 51.5 to 66.5 cM in the OOA, and between 53.9 and 62.7 cM for ASHK. Results from QTL multipoint linkage analyses after combining families from both populations are shown in Figure 2. Three linkage peaks were identified in the VC analysis: LOD= 4.99 at ~55 cM (24.3 Mb); LOD=5.04 at ~62 cM (31 Mb); and LOD=4.97 at ~66.5 cM (34.6 Mb). Three local linkage peaks were also found in the REG analyses: LOD=3.901 at ~54 cM (23.7 Mb); LOD=5.296 at ~60.6 cM (30.7 Mb); and LOD=5.054 at ~66 cM (34.3 Mb). All local linkage signals in the combined analysis were highly statistically significant (all p<10-5).

Bottom Line: 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.Combined analyses showed three highly significant linkage peaks, separated by approximately 11cM (or 10 Mb), within the candidate region.The area of linkage has been narrowed down to a gene-rich region at 1p34.2-35.1 containing ~124 genes.

View Article: PubMed Central - PubMed

Affiliation: Inherited Disease Research Branch, National Human Genome Research Institute, 333 Cassell Drive, Baltimore, MD 21224, USA. robwoj@mail.nih.gov

ABSTRACT

Purpose: 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.

Methods: 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 (approximately 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.

Results: Evidence of linkage of refractive error was found in both OOA (VC LOD=3.45, REG LOD=3.38 at approximately 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 approximately 11cM (or 10 Mb), within the candidate region.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus