Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes

Andrew D. Skol; Segun C. Jung; Ana Marija Sokovic; Siquan Chen; Sarah Fazal; Olukayode Sosina; Poulami P. Borkar; Amy Lin; Maria Sverdlov; Dingcai Cao; Anand Swaroop; Ionut Bebu; Barbara E. Stranger; Michael A. Grassi

doi:10.7554/eLife.59980

Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes

Andrew D. Skol, Segun C. Jung, Ana Marija Sokovic, Siquan Chen, Sarah Fazal, Olukayode Sosina, Poulami P. Borkar, Amy Lin, Maria Sverdlov, Dingcai Cao, Anand Swaroop, Ionut Bebu, Barbara E. Stranger^*, Michael A. Grassi^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association with diabetic retinopathy in a genome-wide association study meta-analysis. Expression quantitative trait loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs with diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy. Integrating genetic association with gene expression implicated FLCN as a disease gene for diabetic retinopathy.

Original language	English (US)
Article number	e59980
Pages (from-to)	1-20
Number of pages	20
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.59980
State	Published - Oct 2020

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.59980

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title = "Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes",

abstract = "We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association with diabetic retinopathy in a genome-wide association study meta-analysis. Expression quantitative trait loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs with diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy. Integrating genetic association with gene expression implicated FLCN as a disease gene for diabetic retinopathy.",

author = "Skol, {Andrew D.} and Jung, {Segun C.} and Sokovic, {Ana Marija} and Siquan Chen and Sarah Fazal and Olukayode Sosina and Borkar, {Poulami P.} and Amy Lin and Maria Sverdlov and Dingcai Cao and Anand Swaroop and Ionut Bebu and Stranger, {Barbara E.} and Grassi, {Michael A.}",

note = "Publisher Copyright: {\textcopyright} Skol et al.",

year = "2020",

month = oct,

doi = "10.7554/eLife.59980",

language = "English (US)",

volume = "9",

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journal = "eLife",

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T1 - Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes

AU - Skol, Andrew D.

AU - Jung, Segun C.

AU - Sokovic, Ana Marija

AU - Chen, Siquan

AU - Fazal, Sarah

AU - Sosina, Olukayode

AU - Borkar, Poulami P.

AU - Lin, Amy

AU - Sverdlov, Maria

AU - Cao, Dingcai

AU - Swaroop, Anand

AU - Bebu, Ionut

AU - Stranger, Barbara E.

AU - Grassi, Michael A.

PY - 2020/10

Y1 - 2020/10

N2 - We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association with diabetic retinopathy in a genome-wide association study meta-analysis. Expression quantitative trait loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs with diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy. Integrating genetic association with gene expression implicated FLCN as a disease gene for diabetic retinopathy.

AB - We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association with diabetic retinopathy in a genome-wide association study meta-analysis. Expression quantitative trait loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs with diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy. Integrating genetic association with gene expression implicated FLCN as a disease gene for diabetic retinopathy.

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Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes

Abstract

ASJC Scopus subject areas

UN SDGs

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