Genetics and Genomics of Eye Disease: Advancing to Precision Medicine

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GENETICS AND
GENOMICS OF EYE
DISEASE:

Advancing to Precision Medicine
Copyright
Dedication
Contributors
Preface
Acknowledgments
Part I: Introduction to gene mapping
1
Timeline of key discoveries in ophthalmic genetics
	References
2
Segregation, linkage, GWAS, and sequencing
	Segregation analysis
		Segregation: How is a trait inherited?
		Simple vs. complex segregation analysis
		Advantages of segregation analysis
		Disadvantages of segregation analysis
		Segregation analyses for ocular traits and diseases
	Linkage analysis
		What is genetic linkage?
		Linkage: What genetic variation contributes to a trait?
		Types of linkage analysis
		Advantages of linkage analysis
		Disadvantages of linkage analysis
		Linkage analyses for ocular traits and diseases
	Genome-wide association studies
		What is a GWAS?
		Advantages and disadvantages of GWAS
		Examples of GWAS for eye diseases
	DNA sequencing
		Overview of sequencing technologies: Past to present
		Types of sequencing
		Advantages and disadvantages of sequencing
	References
Part II: Genomics in the eye
3
Whole-exome sequencing and whole-genome sequencing
	Development of NGS technologies
		Illumina sequencing
	Targeted enrichment sequencing
		Targeted enrichment techniques
			Hybridization-based enrichment
			Molecular inversion probes
			Targeted amplicon sequencing
	Whole-exome sequencing
		Commercially available WES kits
		Panel vs WES
	Whole-genome sequencing technologies
		WES vs WGS
		Long-read technologies
			SMRT sequencing by PacBio
			Nanopore sequencing by ONT
			Linked-reads sequencing by 10x Genomics
	WES/WGS data analysis
	Future direction/perspectives
	References
4
RNA sequencing and transcriptome analysis
	History of transcriptome analysis methods
	RNA-Seq
	Library preparation
	Data analysis-Alignment and count generation
	Data analysis-Novel feature detection
	Data analysis-Downstream applications
	RNA-Seq in the eye
	Transcriptome analyses
	Models of disease
	Disease genes and therapeutic targets
	Concluding remarks
	References
5
Noncoding genome in eye disease
	Introduction to the noncoding genome
	MicroRNAs and the eye
	lncRNAs and the eye
	Noncoding RNAs and eye disease
	Age-related macular degeneration
	Diabetic retinopathy
	Glaucoma
	Retinitis pigmentosa
	Retinoblastoma
	Other diseases of the eye
	Concluding remarks
	References
Part III: Mendelian disorders and high penetrant mutations
6
Genetic architecture of inherited retinal disease
	Spectrum and evaluation of the clinical phenotype of IRD
		Inheritance pattern
	Mechanistic pathways culminating in photoreceptor degeneration
		Ciliary transport and intracellular trafficking
		Photoreceptor development
		Phototransduction cascade
		The visual cycle
		Synaptic transmission defects
		Spliceosome complex
		Interphotoreceptor matrix
	Genetic heterogeneity in IRD
		Genetic heterogeneity in monogenic IRDs
		Allelic heterogeneity in IRD
		Incomplete penetrance in RP11
	Mutation spectrum of IRD
		Regulatory and noncoding variants
		Large DNA duplication and deletion in IRD
		Splice-site and alternative transcript variants
	Conclusion
	References
7
Early-onset glaucoma
	Clinical features of JOAG
		Epidemiology of JOAG
		Age of onset
		Myopia
		Intraocular pressure
		Response to therapy
		Optic disc morphology
		Inheritance pattern
	MYOC and JOAG
		MYOC-associated glaucoma clinical phenotype (JOAG)
		MYOC-associated glaucoma clinical phenotype (POAG)
		MYOC pathophysiology
		Case report (MYOC-associated JOAG)
	OPTN and juvenile-onset open-angle glaucoma
		OPTN-associated glaucoma clinical phenotype
		Function of OPTN
		Association between OPTN and ALS
		Effects of OPTN mutations
		Transgenic mouse models of OPTN-associated glaucoma
		Knock-in mouse model of OPTN-associated glaucoma
		Case report (OPTN-associated glaucoma)
	TBK1 and JOAG
		TBK1-associated glaucoma clinical phenotype
		Function of TBK1
		Effects of TBK1 duplications
		Transgenic mouse model of TBK1-associated glaucoma
		Case report (TBK1-associated glaucoma)
	Genetic testing and JOAG
	Gene-directed therapies
		Targeted therapies for MYOC-associated glaucoma
		OPTN and TBK1-associated glaucoma direct therapies
	Acknowledgments
	References
8
Bardet-Biedl syndrome
	Bardet-Biedl syndrome
		Mode of inheritance
		Clinical diagnosis
		Pleotropic phenotypes
	Retinal degeneration in BBS
		Using animal models to study retinal degeneration in BBS
		In vitro molecular mechanisms of BBS
		Transcriptional variation
	Other disorders attributed to BBS genes
		Leber congenital amaurosis
		Joubert syndrome
		Senior-Løken syndrome
		Nonsyndromic retinal degeneration
	BBS research and advancing biotechnology
	Conclusions
	References
9
Hereditary predisposition to uveal melanoma
	Introduction
	Genetic versus environmental basis of UM
	Familial uveal melanoma
	UM clustering with other cancers
	Highly penetrance genes with reported germline mutations in UM
		BRCA1-associated protein 1 (BAP1)
		Breast cancer 2 (BRCA2)
		Mismatch repair genes (MLH1 and MSH6)
		MBD4
		Birt-Hogg-Dube Syndrome and UM (FLCN)
		CDKN2A/ARF and CDK4
	Low penetrant genes
		HERC2/OCA2
		TERT/CLPTM1L
	Summary and conclusions
	References
Part IV: Complex disorders and low effect-size risk factors
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Age-related macular degeneration
	Introduction
	Genomic studies in AMD
		Genome-wide association studies
		Case-control studies for rare variants
		Family-based studies for rare variants
		Effect sizes of common versus rare variants
		Contribution of common versus rare variants
		Functional effect of common versus rare variants
	Effect of AMD-associated variants on disease mechanisms
		Effect of the common CFH p.Tyr402His variant
		Effect of common variants at the ARMS2/HTRA1 locus
		Effect of genetic variants on gene expression
		Effect of genetic variants on the complement system
		Effect of genetic variants on lipoprotein homeostasis
		Effect of variants on extracellular matrix remodeling
		Effect of variants on neovascularization
	Other omics studies in AMD
	Effect of genetic variants on treatment response
		Dietary supplementation
		Anti-VEGF treatment
		Complement inhibitors
	Conclusions
	Acknowledgments
	References
11
Genetics of primary open-angle glaucoma
	Introduction
		Primary open-angle glaucoma
		Symptoms and diagnosis
		Therapies
	POAG genetics
		Linkage analyses
			MYOC, ASB10, and EFEMP1
			Interleukin 20 receptor subunit β
			Optineurin and TANK-binding kinase 1
			WD repeat domain 36
			Neurotrophin 4
		Genome-wide association studies
			Caveolins 1 and 2
			Transmembrane and coiled-coil domain 1
			CDKN2B antisense RNA 1
			SIX homeobox 6
			ATP-binding cassette subfamily A member 1
			GDP-mannose 4,6-dehydratase and forkhead box C1
			Actin filament-associated protein 1
			Thioredoxin reductase 2
			Ataxin 2
		Endophenotypes
			Intraocular pressure
			Central cornea thickness
			Vertical CDR
			RNFL thickness
		POAG pathways
	Conclusion
	References
12
 Genetics of diabetic retinopathy
	Genetic linkage analysis
	Candidate gene studies
		Aldose reductase
		Endothelial nitric oxide synthase
		Receptor for advanced glycation end products
		Vascular endothelial growth factor
			rs2010963
			rs833061
			rs699947
			rs3025039
			Other VEGF polymorphisms
		Other candidate genes
			Insulin receptor
			Angiotensin-converting enzyme
			Growth factor receptor-bound protein 2
			C-reactive protein
			P-selectin
			High-mobility-group A1
			Solute carrier family 19 member 2/3
	Genome-wide association studies
	Whole-exome sequencing
	Epigenetics
		DNA methylation
		Histone modifications
		MicroRNAs
	Mitochondrial DNA
	Summary
	Acknowledgments
	References
13
Genetics of keratoconus
	Introduction
		Human cornea anatomy
		Keratoconus
			Clinical signs and diagnosis
			Treatment modalities
	Genetics of KC
		Genome-wide linkage studies in KC
		Genome-wide association studies in KC
		KC candidate genes identified by Sanger sequencing or targeted genotyping
	Conclusion
	Conflict of Interest
	References
Part V: Genetic testing and genetic risk prediction
14
Genetic testing of various eye disorders
	Overview of genetic techniques
	Detecting coding variation
	Variants leading to aberrant splicing captured by targeted panels
	Deep-intronic variants
	Variants leading to altered gene expression
	Detecting structural variants (CNV and chromosomal aberration)
	Genetic modifiers of phenotypic severity of IRDs
	Ocular phenotype-A marker of syndromic disease
	Conclusions
	References
15
Genetic risk scores in complex eye disorders
	Introduction
	Risk scores and their applications
	Ocular traits with well-established risk loci and risk scores
		Age-related macular degeneration
			Genetics of AMD
			Risk scores in AMD
		Glaucoma
			Genetics of glaucoma
			Risk scores in glaucoma
		Myopia and refractive error
			Genetics of myopia and refractive error
			Risk scores in myopia and refractive error
	Other complex ocular traits
		Age-related cataract and diabetic retinopathy
		Fuchs endothelial corneal dystrophy (FECD)
	Looking forward: capabilities and limitations of risk scores
		Polygenic risk scores
		Clinical utility of risk scores
	References
Part VI: Gene-based therapy
16
Gene therapy for inherited retinal diseases
	Introduction
	History
	Vectors
	Current studies
		Nonsyndromic RP
			RPGR
			RLBP1
			PDE6ß
			MERTK
		Syndromic RP
			Usher syndrome
			Bardet-Biedl syndrome
		Stargardt disease
		X-linked retinoschisis
		Achromatopsia
		Choroideremia
		Leber congenital amaurosis
	Limitations of gene therapy
	Future perspectives
	References
17
Gene therapy in animal models
	Introduction
	Inherited retinal degenerations
		Classification
			Type of dystrophy
			Clinical nomenclature
		Basic biology of common IRDs
	Animal models of inherited retinal degenerations
		Vertebrate models of IRD
		Gene therapies of IRDs
	Challenges
	References
Part VII: Big data and precision medicine
18
Pleiotropy in eye disease and related traits
	Introduction
	Numerous genes show pleiotropic effects
	GWAS SNPs show pleiotropic effects
	Genetic risk scores show pleiotropic effects
	Implications for genomic medicine
	Other aspects of pleiotropy
	Conclusions
	Acknowledgments
	References
	Web Resources
19
Advancing to precision medicine through big data and artificial intelligence
	Introduction
	Precision medicine
	Advancing precision medicine with big data
	Spearheading precision medicine with AI
	Ancient wisdom on medicine
	Conclusion
	References
Index
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