Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness

Abstract Objective To prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT). Methods We applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analyses were done for participants of European and East Asian ancestries, separately. Results We identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR = 4.15 × 10− 12), PTGDS (ILMN_1664464; PSMR = 6.88 × 10− 9) and C9orf142 (ILMN_1761138; PSMR = 8.09 × 10− 9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4 (ENSG00000273142.1; PSMR = 5.89 × 10− 9), LCNL1 (ENSG00000214402.6; PSMR = 5.67 × 10− 8), and PTGDS (ENSG00000107317.7; PSMR = 1.92 × 10− 7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing. Conclusion We identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.

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Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness

10.1101/2021.02.27.21252574 ◽

2021 ◽

Author(s):

Zhikun Yang ◽

Jingyun Yang ◽

Di Liu ◽

Weihong Yu

Keyword(s):

Multiple Testing ◽

Central Corneal Thickness ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Open Angle Glaucoma ◽

East Asian ◽

Corneal Thickness ◽

European Ancestry ◽

Genome Wide ◽

Eqtl Data

AbstractObjectiveTo prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT).MethodsWe applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analysis were done for participants of European and East Asian ancestries, separately.ResultsWe identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR=4.15×10−12), PTGDS (ILMN_1664464; PSMR=6.88×10−9) and C9orf142 (ILMN_1761138; PSMR=8.09×10−9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4(ENSG00000273142.1; PSMR=5.89×10−9), LCNL1 (ENSG00000214402.6; PSMR=5.67×10−8), and PTGDS (ENSG00000107317.7; PSMR=1.92×10−7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing.ConclusionWe identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.

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Mendelian randomization analysis identified genes potentially pleiotropically associated with periodontitis

10.1101/2021.02.05.21251192 ◽

2021 ◽

Author(s):

Feng Wang ◽

Di Liu ◽

Yong Zhuang ◽

Bowen Feng ◽

Wenjin Lu ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

East Asian ◽

European Ancestry ◽

Asian Ancestry ◽

Multiple Genes ◽

Genome Wide ◽

Eqtl Data ◽

Summary Data ◽

East Asian Ancestry

AbstractObjectiveTo prioritize genes that were pleiotropically or potentially causally associated with periodontitis.MethodsWe applied the summary data-based Mendelian randomization (SMR) method integrating genome-wide association study (GWAS) for periodontitis and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with periodontitis. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analysis were done for participants of European and East Asian ancestries, separately.ResultsWe identified multiple genes showing pleiotropic association with periodontitis in participants of European ancestry and participants of East Asian ancestry. PDCD2 (corresponding probe: ILMN_1758915) was the top hit showing pleotropic association with periodontitis in participants of European ancestry, and BX093763 (corresponding probe: ILMN_1899903) and AC104135.3 (corresponding probe: ENSG00000204792.2) were the top hits in participants of East Asian ancestry using CAGE eQTL data and GTEx eQTL data, respectively.ConclusionWe identified multiple genes that may be involved in the pathogenesis of periodontitis in participants of European ancestry and participants of East Asian ancestry. Our findings provided important leads to a better understanding of the mechanisms underlying periodontitis and revealed potential therapeutic targets for the effective treatment of periodontitis.

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Family-Based Genome-Wide Association Study of South Indian Pedigrees SupportsWNT7Bas a Central Corneal Thickness Locus

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.17-23536 ◽

2018 ◽

Vol 59 (6) ◽

pp. 2495 ◽

Cited By ~ 3

Author(s):

Bao Jian Fan ◽

Xueli Chen ◽

Nisha Sondhi ◽

P. Ferdinamarie Sharmila ◽

Nagasamy Soumittra ◽

...

Keyword(s):

Association Study ◽

Central Corneal Thickness ◽

Genome Wide Association Study ◽

Corneal Thickness ◽

Genome Wide Association ◽

South Indian ◽

Genome Wide ◽

Family Based

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Mendelian randomization analysis identified potential genes pleiotropically associated with polycystic ovary syndrome

10.1101/2021.06.29.21259512 ◽

2021 ◽

Author(s):

Qian Sun ◽

Yuan Gao ◽

Jingyun Yang ◽

Jiayi Lu ◽

Wen Feng ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Whole Blood ◽

Multiple Testing ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Polycystic Ovary ◽

Research Question ◽

Ovary Syndrome ◽

Unclear Etiology ◽

Eqtl Data

Research question: Polycystic ovary syndrome (PCOS) is a common endocrine disorder with unclear etiology. Are there any genes that are pleiotropically or potentially causally associated with PCOS? Design: We applied the summary data-based Mendelian randomization (SMR) method integrating genome-wide association study (GWAS) for PCOS and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with PCOS. We performed separate SMR analysis using eQTL data in the ovary and whole blood. Results: Although no genes showed significant pleiotropic association with PCOS after correction for multiple testing, some of the genes exhibited suggestive significance. RPS26 showed the strongest suggestive pleiotropic association with PCOS in both SMR analyses (β[SE]=0.10[0.03], PSMR=1.72*10-4 for ovary; β[SE]=0.11[0.03], PSMR=1.40*10-4 for whole blood). PM20D1 showed the second strongest suggestive pleiotropic association with PCOS in the SMR analysis using eQTL data for the whole blood, and was also among the top ten hit genes in the SMR analysis using eQTL data for the ovary. Two other genes, including CTC-457L16.2 and NEIL2, were among the top ten hit genes in both SMR analyses. Conclusion: We identified multiple genes that were potentially involved in the pathogenesis of PCOS. Our findings provided helpful leads to a better understanding of the mechanisms underlying PCOS, and revealed potential therapeutic targets for the effective treatment of PCOS.

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Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Communications Biology ◽

10.1038/s42003-019-0634-9 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 2

Author(s):

Pieter W. M. Bonnemaijer ◽

◽

Elisabeth M. van Leeuwen ◽

Adriana I. Iglesias ◽

Puya Gharahkhani ◽

...

Keyword(s):

Genome Wide Association Study ◽

Open Angle Glaucoma ◽

Association Studies ◽

Corneal Thickness ◽

Genome Wide Association ◽

Joint Analysis ◽

Genome Wide Association Studies ◽

Multiple Traits ◽

Trait Analysis ◽

Genome Wide

AbstractA new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

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A Genome-Wide Association Study of Central Corneal Thickness in Latinos

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.13-11692 ◽

2013 ◽

Vol 54 (4) ◽

pp. 2435 ◽

Cited By ~ 30

Author(s):

Xiaoyi Gao ◽

W. James Gauderman ◽

Yutao Liu ◽

Paul Marjoram ◽

Mina Torres ◽

...

Keyword(s):

Association Study ◽

Central Corneal Thickness ◽

Genome Wide Association Study ◽

Corneal Thickness ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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A causal association between schizophrenia and bipolar disorder on rheumatoid arthritis: A two-sample Mendelian randomization study

10.1101/2021.08.12.21261493 ◽

2021 ◽

Author(s):

Gonul Hazal Koc ◽

Fatih Ozel ◽

Kaan Okay ◽

Dogukan Koc

Keyword(s):

Rheumatoid Arthritis ◽

Bipolar Disorder ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Causal Association ◽

Genome Wide ◽

Inverse Variance ◽

Weighted Median

Background: Schizophrenia(SCZ) and bipolar disorder(BD) are both associated with several autoimmune/inflammatory disorders including rheumatoid arthritis(RA). However, a causal association of SCZ and BD on RA is controversial and elusive. In the present study, we aimed to investigate the causal association of SCZ and BD with RA by using the Mendelian randomization (MR) approach. Methods: A two-sample MR(2SMR) study including the inverse-variance weighted(IVW), weighted median, simple mode, weighted mode and MR-Egger methods were performed. We employed summary-level genome-wide association study(GWAS) data including BD and SCZ as exposure and RA as an outcome. We utilized data from the Psychiatric Genomics Consortium(PGC) for BD(n= 41,917) and SCZ(n= 33,426), whereas RA GWAS dataset (58,284 individuals) from the European ancestry. Results: We obtained independent (r2 <0.001) 48 and 52 single nucleotide polymorphisms (SNPs) from BD and SCZ data at genome-wide significance (p <5x10-8), respectively. Next, these SNPs were utilized as instrumental variables(IVs) in 2SMR analysis to explore the causality of BD and SCZ on RA. The two out of five MR methods showed a statistically significant inverse causal association between BD and RA: weighted median method(odds ratio (OR), 0.869, [95% CI, 0.764-0.989]; P= 0.034) and inverse-variance weighted(IVW) method (OR, 0.810, [95% CI, 0.689-0.953]; P= 0.011). However, we did not find any significant association of SCZ with RA (OR, 1.008, [95% CI, 0.931-1.092]; P= 0.829, using the IVW method). Conclusions: These results provide support for an inverse causal association between BD and RA. Further investigation is needed to explain the underlying protective mechanisms in the development of RA.

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Multi-Ancestry Meta-Analysis yields novel genetic discoveries and ancestry-specific associations

10.1101/2021.04.23.441003 ◽

2021 ◽

Author(s):

Patrick Turley ◽

Alicia R. Martin ◽

Grant Goldman ◽

Hui Li ◽

Masahiro Kanai ◽

...

Keyword(s):

Error Rate ◽

Genome Wide Association Study ◽

Meta Analysis ◽

East Asian ◽

Genome Wide Association ◽

European Ancestry ◽

Summary Statistics ◽

Type 1 Error ◽

Genome Wide

ABSTRACTWe present a new method, Multi-Ancestry Meta-Analysis (MAMA), which combines genome-wide association study (GWAS) summary statistics from multiple populations to produce new summary statistics for each population, identifying novel loci that would not have been discovered in either set of GWAS summary statistics alone. In simulations, MAMA increases power with less bias and generally lower type-1 error rate than other multi-ancestry meta-analysis approaches. We apply MAMA to 23 phenotypes in East-Asian- and European-ancestry populations and find substantial gains in power. In an independent sample, novel genetic discoveries from MAMA replicate strongly.

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