Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families.
Chromosomes, Human
/ genetics
Chromosomes, Human, Pair 1
/ genetics
Chromosomes, Human, Pair 11
/ genetics
Chromosomes, Human, Pair 7
/ genetics
Chromosomes, Human, Pair 8
/ genetics
Exome
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotyping Techniques
/ methods
Humans
Jews
/ genetics
Lod Score
Male
Myopia
/ ethnology
Pedigree
RNA, Long Noncoding
/ genetics
Family studies
Genetic linkage
Myopia
Journal
BMC medical genetics
ISSN: 1471-2350
Titre abrégé: BMC Med Genet
Pays: England
ID NLM: 100968552
Informations de publication
Date de publication:
31 01 2019
31 01 2019
Historique:
received:
04
10
2018
accepted:
11
01
2019
entrez:
2
2
2019
pubmed:
2
2
2019
medline:
21
8
2019
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30704416
doi: 10.1186/s12881-019-0752-8
pii: 10.1186/s12881-019-0752-8
pmc: PMC6357511
doi:
Substances chimiques
LINC00339 long noncoding RNA, human
0
RNA, Long Noncoding
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Pagination
27Subventions
Organisme : National Eye Institute
ID : R01 EY020483
Pays : United States
Références
Nat Commun. 2016 Mar 29;7:11008
pubmed: 27020472
J Med Genet. 2002 Feb;39(2):118-24
pubmed: 11836361
Nat Genet. 2013 Mar;45(3):314-8
pubmed: 23396134
Hum Mol Genet. 2013 Jul 1;22(13):2754-64
pubmed: 23474815
PLoS One. 2013;8(3):e58257
pubmed: 23472165
Mol Vis. 2008;14:2566-74
pubmed: 19122830
Ophthalmology. 2005 Jan;112(1):78-83
pubmed: 15629824
Mol Vis. 2007 Jun 28;13:1012-9
pubmed: 17653045
Ophthalmology. 2008 Jun;115(6):1053-1057.e2
pubmed: 17964656
Clin Genet. 2013 Aug;84(2):102-8
pubmed: 23647423
Genome Res. 2007 Dec;17(12):1783-6
pubmed: 17989245
Mol Vis. 2009 Nov 05;15:2239-48
pubmed: 19907666
Invest Ophthalmol Vis Sci. 2011 Jun 01;52(6):3500-5
pubmed: 21421876
Sci Rep. 2016 May 13;6:25853
pubmed: 27174397
Genet Epidemiol. 2006 Nov;30(7):620-6
pubmed: 16868964
Am J Hum Genet. 2013 Aug 8;93(2):264-77
pubmed: 24144296
Am J Hum Genet. 2004 Aug;75(2):294-304
pubmed: 15307048
Am J Hum Genet. 2004 Sep;75(3):448-59
pubmed: 15273935
Genet Epidemiol. 2008 Jul;32(5):454-63
pubmed: 18293391
Nat Protoc. 2015 Oct;10(10):1556-66
pubmed: 26379229
PLoS Genet. 2013 Apr;9(4):e1003442
pubmed: 23593034
Mol Vis. 2009;15:312-8
pubmed: 19204786
Invest Ophthalmol Vis Sci. 2009 Jan;50(1):47-56
pubmed: 19124844
Optom Vis Sci. 2014 Apr;91(4):419-29
pubmed: 24637479
Hum Mol Genet. 2016 Nov 15;25(22):5046-5058
pubmed: 28171565
PLoS One. 2011 May 12;6(5):e19587
pubmed: 21589860
Genet Med. 2015 Apr;17(4):300-6
pubmed: 25741866
Nat Genet. 2010 Oct;42(10):897-901
pubmed: 20835239
J Med Genet. 2012 Jul;49(7):433-6
pubmed: 22717648
Mol Vis. 2006 Dec 04;12:1499-505
pubmed: 17167407
Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53
pubmed: 18158296
Invest Ophthalmol Vis Sci. 2001 May;42(6):1232-6
pubmed: 11328732
BMC Med Genet. 2004 Aug 03;5:20
pubmed: 15291966
Hum Genet. 2006 May;119(4):389-99
pubmed: 16501916
J Med Genet. 2016 May;53(5):318-29
pubmed: 27095636
Am J Hum Genet. 1996 Jun;58(6):1323-37
pubmed: 8651310
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
PLoS Genet. 2008 Oct;4(10):e1000220
pubmed: 18846214
Int J Mol Epidemiol Genet. 2013 Nov 28;4(4):193-206
pubmed: 24319535
Ophthalmic Genet. 2012 Sep;33(3):171-8
pubmed: 22809227
Nat Genet. 2002 Jan;30(1):97-101
pubmed: 11731797
Mol Vis. 2013;19:243-53
pubmed: 23401653
Nat Genet. 1995 Nov;11(3):241-7
pubmed: 7581446
Am J Hum Genet. 2014 Jan 2;94(1):33-46
pubmed: 24360806
Bioinformatics. 2005 Jan 15;21(2):263-5
pubmed: 15297300
Ophthalmic Genet. 2007 Sep;28(3):179-82
pubmed: 17896318
J Neurol Sci. 2016 Apr 15;363:43-50
pubmed: 27000219
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Clin Ophthalmol. 2015 Oct 27;9:2005-11
pubmed: 26604670
Eur J Hum Genet. 2015 Dec;23(12):1739-43
pubmed: 25873013
Invest Ophthalmol Vis Sci. 2011 Jul 13;52(8):5220-5
pubmed: 21571680
PLoS One. 2014 Sep 18;9(9):e107110
pubmed: 25233373
J Med Genet. 2014 Aug;51(8):518-25
pubmed: 24891338
Int Rev Cytol. 2003;230:1-39
pubmed: 14692680
Am J Hum Genet. 2002 Feb;70(2):496-508
pubmed: 11791215
Am J Hum Genet. 2010 Jul 9;87(1):123-8
pubmed: 20598280
Eye (Lond). 2008 Apr;22(4):576-81
pubmed: 17948041
Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4421-5
pubmed: 17898260
Hum Mol Genet. 2011 Sep 15;20(18):3693-8
pubmed: 21665993
Hum Hered. 2001;52(3):121-31
pubmed: 11588394
Mol Vis. 2015 Mar 05;21:213-23
pubmed: 25802485
PLoS One. 2013;8(1):e48495
pubmed: 23341868
Genome Biol. 2010;11(8):R90
pubmed: 20799968