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Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep.

Mousel MR, Reynolds JO, White SN - PLoS ONE (2015)

Bottom Line: Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model).This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge.Further, none of these genes have previously been associated with any eyelid traits.

View Article: PubMed Central - PubMed

Affiliation: Range Sheep Production Efficiency Research Unit, Agricultural Research Service, Department of Agriculture, Dubois, ID, United States of America.

ABSTRACT
Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10(-5)) were identified including markers in or near PIK3CB (P = 2.22x10(-6); additive model), KCNB1 (P = 2.93x10(-6); dominance model), ZC3H12C (P = 3.25x10(-6); genotypic model), JPH1 (P = 4.68x20(-6); genotypic model), and MYO3B (P = 5.74x10(-6); recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection.

No MeSH data available.


Related in: MedlinePlus

Genotypic Manhattan plot for entropion.The Manhattan plot shows nominal P-values from association with entropion by chromosomal position. Data from genotypic mode of inheritance analyses. The top red line shows a genome-wide significance threshold defined by nominal P-values of 1x10-6, which is P = 0.05/50,000. The lower blue line shows a genome-wide suggestive significance threshold (1x10-5).
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pone.0128909.g001: Genotypic Manhattan plot for entropion.The Manhattan plot shows nominal P-values from association with entropion by chromosomal position. Data from genotypic mode of inheritance analyses. The top red line shows a genome-wide significance threshold defined by nominal P-values of 1x10-6, which is P = 0.05/50,000. The lower blue line shows a genome-wide suggestive significance threshold (1x10-5).

Mentions: Manhattan plots showing P-values in order of chromosome position, from the genotypic and dominant analysis, are presented in Fig 1 and Fig 2, respectively. Two SNP were classified as genome-wide significant and six SNP were genome-wide suggestive (Table 1). Observed vs expected P-value distributions were visualized in quantile-quantile plots from genotypic analyses with all SNP (Fig 3) and the conditioned on the following 5 SNP, rs424438792, rs420662001, rs420083564, rs419388939, and rs405483139, (Fig 4). Fig 3 shows some of the observed P-values were divergent from the expected line indicating possible population stratification, including potentially differing frequencies of a small number of genetic mutations. Nearly all stratification is eliminated after conditioning the analysis on the 5 SNP shown above (Fig 4). This demonstrates that the apparent population stratification was due to differences in allele frequencies of SNP associated with entropion. Dominant analysis quantile-quantile plots with all SNP and conditioned on the above 5 SNP are shown in S2 Fig and S3 Fig. The genotype count for the top 8 SNP by breed and entropion status are shown in S1 Table and the raw data for these SNP may be found at: http://www.ncbi.nlm.nih.gov/projects/SNP/snp_viewBatch.cgi?ibid=1062140 or http://www.animalgenome.org/repository/pub/USDA2015.0208/ Threshold analysis showed rs424438792, rs720662001, rs420083564, rs703034846, rs419388939, and rs405483139 significantly (P < 0.04) and rs415069937 and rs401620279 were not (P > 0.06) associated with entropion. The sheep genome assemble Oar_v3.1 [26] was used to determine the location of the top 8 SNP associated with entropion which were found to be located within or near the following genes: solute carrier family 2 C 9 (SLC2A9, a.k.a. GLUT9), phosphatidylinositol 4,5-bisphospate 3-kinase, catalytic subunit beta isoform (PIK3CB), myosin-IIIb (MYO3B), potassium voltage-gated channel subfamily B member 1 (KCNB1), neurolysin (NLN), zinc finger CCCH-type containing 12C (ZC3H12C), and junctophilin 1 (JPH1).


Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep.

Mousel MR, Reynolds JO, White SN - PLoS ONE (2015)

Genotypic Manhattan plot for entropion.The Manhattan plot shows nominal P-values from association with entropion by chromosomal position. Data from genotypic mode of inheritance analyses. The top red line shows a genome-wide significance threshold defined by nominal P-values of 1x10-6, which is P = 0.05/50,000. The lower blue line shows a genome-wide suggestive significance threshold (1x10-5).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476619&req=5

pone.0128909.g001: Genotypic Manhattan plot for entropion.The Manhattan plot shows nominal P-values from association with entropion by chromosomal position. Data from genotypic mode of inheritance analyses. The top red line shows a genome-wide significance threshold defined by nominal P-values of 1x10-6, which is P = 0.05/50,000. The lower blue line shows a genome-wide suggestive significance threshold (1x10-5).
Mentions: Manhattan plots showing P-values in order of chromosome position, from the genotypic and dominant analysis, are presented in Fig 1 and Fig 2, respectively. Two SNP were classified as genome-wide significant and six SNP were genome-wide suggestive (Table 1). Observed vs expected P-value distributions were visualized in quantile-quantile plots from genotypic analyses with all SNP (Fig 3) and the conditioned on the following 5 SNP, rs424438792, rs420662001, rs420083564, rs419388939, and rs405483139, (Fig 4). Fig 3 shows some of the observed P-values were divergent from the expected line indicating possible population stratification, including potentially differing frequencies of a small number of genetic mutations. Nearly all stratification is eliminated after conditioning the analysis on the 5 SNP shown above (Fig 4). This demonstrates that the apparent population stratification was due to differences in allele frequencies of SNP associated with entropion. Dominant analysis quantile-quantile plots with all SNP and conditioned on the above 5 SNP are shown in S2 Fig and S3 Fig. The genotype count for the top 8 SNP by breed and entropion status are shown in S1 Table and the raw data for these SNP may be found at: http://www.ncbi.nlm.nih.gov/projects/SNP/snp_viewBatch.cgi?ibid=1062140 or http://www.animalgenome.org/repository/pub/USDA2015.0208/ Threshold analysis showed rs424438792, rs720662001, rs420083564, rs703034846, rs419388939, and rs405483139 significantly (P < 0.04) and rs415069937 and rs401620279 were not (P > 0.06) associated with entropion. The sheep genome assemble Oar_v3.1 [26] was used to determine the location of the top 8 SNP associated with entropion which were found to be located within or near the following genes: solute carrier family 2 C 9 (SLC2A9, a.k.a. GLUT9), phosphatidylinositol 4,5-bisphospate 3-kinase, catalytic subunit beta isoform (PIK3CB), myosin-IIIb (MYO3B), potassium voltage-gated channel subfamily B member 1 (KCNB1), neurolysin (NLN), zinc finger CCCH-type containing 12C (ZC3H12C), and junctophilin 1 (JPH1).

Bottom Line: Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model).This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge.Further, none of these genes have previously been associated with any eyelid traits.

View Article: PubMed Central - PubMed

Affiliation: Range Sheep Production Efficiency Research Unit, Agricultural Research Service, Department of Agriculture, Dubois, ID, United States of America.

ABSTRACT
Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10(-5)) were identified including markers in or near PIK3CB (P = 2.22x10(-6); additive model), KCNB1 (P = 2.93x10(-6); dominance model), ZC3H12C (P = 3.25x10(-6); genotypic model), JPH1 (P = 4.68x20(-6); genotypic model), and MYO3B (P = 5.74x10(-6); recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection.

No MeSH data available.


Related in: MedlinePlus