A common variant near TGFBR3 is associated with primary open angle glaucoma

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

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Abstract Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array ), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, OR G-allele = 1.13, P meta = 1.60 × 10 −8 ). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

Multiple linear regression analysis for the SNPs with AL, CCT, VCDR and IOP as dependant variable in the whole cohort.

<p>^Ω = <i>P(</i>β± SE)</p><p>β = standard regression coefficient; SE = standard error; AL-axial length; CCT- Central corneal thickness, VCDR-vertical cup to disc ratio, IOP- intra ocular pressure.</p><p>*Obtained from linear regression, adjusted for age and gender</p><p>Bonferroni adjusted significant level< = 0.008 (0.05/6). Variation in no of samples depends on the availability of data.</p><p>Multiple linear regression analysis for the SNPs with AL, CCT, VCDR and IOP as dependant variable in the whole cohort.</p

Analysis of minor allele frequencies and χ^<b>2</b> of the SNPs between POAG and controls.

<p>M- Major allele, m-minor allele</p><p>* <i>P</i> values are derived from χ² tests; significance: P<0.05</p><p>Analysis of minor allele frequencies and χ^<b>2</b> of the SNPs between POAG and controls.</p

Demographic and clinical features of the study subjects.

<p>*the age at recruitment for controls or age of disease onset for POAG patients are shown</p><p>SD-standard deviation, IOP- intraocular pressure, VCDR-vertical cup to disc ratio, CCT- central corneal thickness, AL- axial length, ACD- anterior chamber depth.</p><p>Demographic and clinical features of the study subjects.</p

Association of the SNPs with CCT, VCDR, IOP, AL in controls and POAG (HTG/NTG/combined).

<p>β = standard regression coefficient</p><p>SE = standard error</p><p>£- dominant model</p><p>∞- recessive model</p><p>¶-additive model</p><p>*Obtained from linear regression</p><p>Bonferroni adjusted significant level< = 0.008 (0.05/6)</p><p>Association of the SNPs with CCT, VCDR, IOP, AL in controls and POAG (HTG/NTG/combined).</p

Genetic Association of SNPs near <i>ATOH7</i>, <i>CARD10</i>, <i>CDKN2B</i>, <i>CDC7</i> and <i>SIX1/SIX6</i> with the Endophenotypes of Primary Open Angle Glaucoma in Indian Population

<div><p>Primary open angle glaucoma (POAG) belonging to a group of optic neuropathies, result from interaction between genetic and environmental factors. Study of associations with quantitative traits (QTs) is one of the successful strategies to understand the complex genetics of POAG. The current study attempts to explore the association of variations near/in genes like <i>ATOH7</i>, <i>SIX1/SIX6</i> complex, <i>CDKN2B</i>, <i>CARD10</i>, and <i>CDC7</i> with POAG and its QTs including vertical cup to disc ratio (VCDR), central corneal thickness (CCT), intra ocular pressure (IOP), and axial length (AL). Case-control study design was carried out in a sample size of 97 POAG cases and 371 controls from South India. Model-based (additive, recessive, dominant) association of the genotypes and their interaction was carried out between cases and controls using chi-square, linear and logistic regression methods. Nominal significance (<i>P</i><0.05) was observed for QTs like i) VCDR with SNPs rs1900004 (<i>ATOH7</i>); rs1192415 (<i>CDC7)</i>; rs10483727 (<i>SIX1/SIX6)</i>, rs9607469 (<i>CARD10);</i> ii) CCT with rs1192415; iii) IOP with rs1900004 and iv) AL with rs1900004 and rs1063192 (<i>CDKN2B)</i>. We were able to replicate previously known interactions between <i>ATOH7-SIX6</i> and <i>SIX6-CDKN2B</i> along with few novel interactions between <i>ATOH7</i>—<i>CDC7</i> and <i>SIX6</i> with genes including <i>CARD10</i> and <i>CDC7</i>. In summary, our results suggest that a probable interaction among the candidate genes for QTs, play a major role in determining the individual’s susceptibility to POAG.</p></div