Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families

Claire Simpson, Anthony M. Musolf, Qing Li, Laura Portas, Federico Murgia, Roberto Y. Cordero, Jennifer B. Cordero, Bilal A. Moiz, Emily R. Holzinger, Candace D. Middlebrooks, Deyana D. Lewis, Joan E. Bailey-Wilson, Dwight Stambolian

Research output: Contribution to journalArticle

Abstract

Background: Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. Methods: Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. Results: Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. Conclusions: We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.

Original languageEnglish (US)
Article number27
JournalBMC Medical Genetics
Volume20
Issue number1
DOIs
StatePublished - Jan 31 2019

Fingerprint

Exome
Myopia
Refractive Errors
Haplotypes
Genome
Genes
Chromosomes, Human, Pair 8
Chromosomes, Human, Pair 11
Genetic Linkage
Chromosomes, Human, Pair 7
Eye Diseases
Chromosomes, Human, Pair 1
Information Storage and Retrieval
Microsatellite Repeats
Genotype

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families. / Simpson, Claire; Musolf, Anthony M.; Li, Qing; Portas, Laura; Murgia, Federico; Cordero, Roberto Y.; Cordero, Jennifer B.; Moiz, Bilal A.; Holzinger, Emily R.; Middlebrooks, Candace D.; Lewis, Deyana D.; Bailey-Wilson, Joan E.; Stambolian, Dwight.

In: BMC Medical Genetics, Vol. 20, No. 1, 27, 31.01.2019.

Research output: Contribution to journalArticle

Simpson, C, Musolf, AM, Li, Q, Portas, L, Murgia, F, Cordero, RY, Cordero, JB, Moiz, BA, Holzinger, ER, Middlebrooks, CD, Lewis, DD, Bailey-Wilson, JE & Stambolian, D 2019, 'Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families', BMC Medical Genetics, vol. 20, no. 1, 27. https://doi.org/10.1186/s12881-019-0752-8
Simpson, Claire ; Musolf, Anthony M. ; Li, Qing ; Portas, Laura ; Murgia, Federico ; Cordero, Roberto Y. ; Cordero, Jennifer B. ; Moiz, Bilal A. ; Holzinger, Emily R. ; Middlebrooks, Candace D. ; Lewis, Deyana D. ; Bailey-Wilson, Joan E. ; Stambolian, Dwight. / Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families. In: BMC Medical Genetics. 2019 ; Vol. 20, No. 1.
@article{b81099e3cc7c4617b35d894ebd3c98f9,
title = "Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families",
abstract = "Background: Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. Methods: Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. Results: Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. Conclusions: We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.",
author = "Claire Simpson and Musolf, {Anthony M.} and Qing Li and Laura Portas and Federico Murgia and Cordero, {Roberto Y.} and Cordero, {Jennifer B.} and Moiz, {Bilal A.} and Holzinger, {Emily R.} and Middlebrooks, {Candace D.} and Lewis, {Deyana D.} and Bailey-Wilson, {Joan E.} and Dwight Stambolian",
year = "2019",
month = "1",
day = "31",
doi = "10.1186/s12881-019-0752-8",
language = "English (US)",
volume = "20",
journal = "BMC Medical Genetics",
issn = "1471-2350",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families

AU - Simpson, Claire

AU - Musolf, Anthony M.

AU - Li, Qing

AU - Portas, Laura

AU - Murgia, Federico

AU - Cordero, Roberto Y.

AU - Cordero, Jennifer B.

AU - Moiz, Bilal A.

AU - Holzinger, Emily R.

AU - Middlebrooks, Candace D.

AU - Lewis, Deyana D.

AU - Bailey-Wilson, Joan E.

AU - Stambolian, Dwight

PY - 2019/1/31

Y1 - 2019/1/31

N2 - Background: Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. Methods: Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. Results: Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. Conclusions: We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.

AB - Background: Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. Methods: Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. Results: Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. Conclusions: We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.

UR - http://www.scopus.com/inward/record.url?scp=85060890383&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060890383&partnerID=8YFLogxK

U2 - 10.1186/s12881-019-0752-8

DO - 10.1186/s12881-019-0752-8

M3 - Article

VL - 20

JO - BMC Medical Genetics

JF - BMC Medical Genetics

SN - 1471-2350

IS - 1

M1 - 27

ER -