title: Exome-based case-control association study using extreme phenotype design reveals novel candidates with protective effect in diabetic retinopathy.
abstract: Diabetic retinopathy (DR) is a common clinical expression of diabetes mellitus-induced vasculopathy and is a major cause of vision loss. Significant gaps remain in our understanding of the molecular pathoetiology of DR, and it is hoped that human genetic approaches can reveal novel targets especially since DR is a heritable trait. Previous studies have focused on genetic risk factors of DR but their results have been mixed. In this study, we hypothesized that the use of the extreme phenotype design will increase the power of a genomewide search for "protective" genetic variants. We enrolled a small yet atypical cohort of 43 diabetics who did not develop DR a decade or more after diagnosis (cases), and 64 diabetics with DR (controls), all of similar ethnic background (Saudi). Whole-exome sequencing of the entire cohort was followed by statistical analysis employing combined multivariate and collapsing methods at the gene level, to identify genes that are enriched for rare variants in cases vs.
  
  
  METHODS
  Three genes (NME3, LOC728699, and FASTK) reached gene-based genome-wide significance at the 10(-08) threshold (p value = 1.55 × 10(-10), 6.23 × 10(-10), 3.21 × 10(-08), respectively). Our results reveal novel candidate genes whose increased rare variant burden appears to protect against DR, thus highlighting them as attractive candidate targets, if replicated by future studies, for the treatment and prevention of DR. Extreme phenotype design when implemented in sequencing-based genome-wide case-control studies has the potential to reveal novel candidates with a smaller cohort size compared to standard study designs.
authors.affiliation: Population Genomics, Life Sciences Solutions, Thermo Fisher Scientific, Carlsbad, CA, 92008, USA.
authors.forename: Corina
authors.initials: C
authors.lastname: Shtir
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aldahmesh
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saad
authors.initials: S
authors.lastname: Al-Dahmash
authors.affiliation: Retina Department, Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE.
authors.forename: Emad
authors.initials: E
authors.lastname: Abboud
authors.affiliation: Department of Ophthalmology, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.
authors.forename: Hisham
authors.initials: H
authors.lastname: Alkuraya
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Marwan A
authors.initials: MA
authors.lastname: Abouammoh
authors.affiliation: Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Sawsan R
authors.initials: SR
authors.lastname: Nowailaty
authors.affiliation: Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Ghazai
authors.initials: G
authors.lastname: Al-Thubaiti
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Project, Riyadh, Saudi Arabia.
authors.forename: E A
authors.initials: EA
authors.lastname: Naim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Project, Riyadh, Saudi Arabia.
authors.forename: B
authors.initials: B
authors.lastname: ALYounes
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Project, Riyadh, Saudi Arabia.
authors.forename: F S
authors.initials: FS
authors.lastname: Binhumaid
authors.affiliation: Saudi Human Genome Project, Riyadh, Saudi Arabia.|King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: A B
authors.initials: AB
authors.lastname: ALOtaibi
authors.affiliation: Saudi Human Genome Project, Riyadh, Saudi Arabia.|King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: A S
authors.initials: AS
authors.lastname: Altamimi
authors.affiliation: Saudi Human Genome Project, Riyadh, Saudi Arabia.|King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: F H
authors.initials: FH
authors.lastname: Alamer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.affiliation: Saudi Human Genome Project, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Project, Riyadh, Saudi Arabia.
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Saudi Human Genome Project, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.identifier: http://orcid.org/0000-0003-4158-341X
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003930:Diabetic Retinopathy / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015999:Multivariate Analysis; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA
chemical_list: D005819:Genetic Markers; D054778:NM23 Nucleoside Diphosphate Kinases; C095367:FASTK protein, human; D017346:Protein Serine-Threonine Kinases; C517942:NME3 protein, human