Genome‐wide and Phenome‐wide Approaches to Understand Variable Drug Actions in Electronic Health Records

Robinson, Jamie R.; Denny, Joshua C.; Roden, Dan M.; Driest, Sara L. Van

doi:10.1111/cts.12522

Cited by 40 publications

(25 citation statements)

References 105 publications

(225 reference statements)

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“…Through GWASs, thousands of genetic associations have been identified. Investigating whether traits share similar genetic variants may shed new light on biological processes and may have important therapeutic implications, such as drug repositioning (29,30). For our study, the top SNPs associated with macular thickness are also related to other ocular traits, including glaucoma, AMD, myopia, axial length and optic nerve head measurements.…”

Section: Discussionmentioning

confidence: 97%

Genome-wide association analyses identify 139 loci associated with macular thickness in the UK Biobank cohort

Huang

Kim

2018

Human Molecular Genetics

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The macula, located near the center of the retina in the human eye, is responsible for providing critical functions, such as central, sharp vision. Structural changes in the macula are associated with many ocular diseases, including age-related macular degeneration (AMD) and glaucoma. Although macular thickness is a highly heritable trait, there are no prior reported genome-wide association studies (GWASs) of it. Here we describe the first GWAS of macular thickness, which was measured by spectral-domain optical coherence tomography using 68 423 participants from the UK Biobank cohort. We identified 139 genetic loci associated with macular thickness at genome-wide significance (P < 5 × 10 −8). The most significant loci were LINC00461 (P = 5.1 × 10 −120), TSPAN10 (P = 1.2 × 10 −118), RDH5 (P = 9.2 × 10 −105) and SLC6A20 (P = 1.4 × 10 −71). Results from gene expression demonstrated that these genes are highly expressed in the retina. Other hits included many previously reported AMD genes, such as NPLOC4 (P = 1.7 × 10 −103), RAD51B (P = 9.1 × 10 −14) and SLC16A8 (P = 1.7 × 10 −8), further providing functional significance of the identified loci. Through cross-phenotype analysis, these genetic loci also exhibited pleiotropic effects with myopia, neurodegenerative diseases (e.g. Parkinson's disease, schizophrenia and Alzheimer's disease), cancer (e.g. breast, ovarian and lung cancers) and metabolic traits (e.g. body mass index, waist circumference and type 2 diabetes). Our findings provide the first insight into the genetic architecture of macular thickness and may further elucidate the pathogenesis of related ocular diseases, such as AMD.

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Section: Discussionmentioning

confidence: 97%

Genome-wide association analyses identify 139 loci associated with macular thickness in the UK Biobank cohort

Huang

Kim

2018

Human Molecular Genetics

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“…N aturally occurring variants in the human genome can serve as experiments of nature to study potential drug targets. [1][2][3][4] Individuals with genetic variants detected as single-nucleotide polymorphisms (SNPs) can have profiles similar to individuals receiving a treatment. An example of a gene-drug pair is the interleukin 6 receptor (IL6R) genetic variant Asp358Ala (rs2228145) and the IL6R antagonists tocilizumab and sarilumab.…”

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confidence: 99%

Association of Interleukin 6 Receptor Variant With Cardiovascular Disease Effects of Interleukin 6 Receptor Blocking Therapy

Cai¹,

Zhang²,

Ho³

et al. 2018

JAMA Cardiol

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“…Very recently a new genotype-to-phenotype approach known as phenome-wide association study (PheWAS) has been developed to statistically estimate the association between single-nucleotide polymorphisms and many different phenotypes. 300 This approach is not a substitution of phenotype-to-genotype GWAS approach, but could work complement GWAS as a reliable tools to advance personalized Medicine [300][301][302] This PheWAS approach has re-validatedprior-known genetic variants and diabetes associations, 303 and appears to have application in understanding the complexities of many polygenic disorders. 300 Through this auxiliary PheWAS approach, further crucial steps in personalized diabetes could be achieved.…”

Section: Phenome-wide Association Studiesmentioning

confidence: 99%

Genetic predisposition in type 2 diabetes: A promising approach toward a personalized management of diabetes

Sirdah

Reading

2020

Clinical Genetics

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Diabetes mellitus, also known simply as diabetes, has been described as a chronic and complex endocrine metabolic disorder that is a leading cause of death across the globe. It is considered a key public health problem worldwide and one of four important non-communicable diseases prioritized for intervention through world health campaigns by various international foundations. Among its four categories, Type 2 diabetes (T2D) is the commonest form of diabetes accounting for over 90% of worldwide cases. Unlike monogenic inherited disorders that are passed on in a simple pattern, T2D is a multifactorial disease with a complex etiology, where a mixture of genetic and environmental factors are strong candidates for the development of the clinical condition and pathology. The genetic factors are believed to be key predisposing determinants in individual susceptibility to T2D. Therefore, identifying the predisposing genetic variants could be a crucial step in T2D management as it may ameliorate the clinical condition and preclude complications. Through an understanding the unique genetic and environmental factors that influence the development of this chronic disease individuals can benefit from personalized approaches to treatment. We searched the literature published in three electronic databases: PubMed, Scopus and ISI Web of Science for the current status of T2D and its associated genetic risk variants and discus promising approaches toward a personalized management of this chronic, non-communicable disorder.

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Genome‐wide and Phenome‐wide Approaches to Understand Variable Drug Actions in Electronic Health Records

Cited by 40 publications

References 105 publications

Genome-wide association analyses identify 139 loci associated with macular thickness in the UK Biobank cohort

Genome-wide association analyses identify 139 loci associated with macular thickness in the UK Biobank cohort

Association of Interleukin 6 Receptor Variant With Cardiovascular Disease Effects of Interleukin 6 Receptor Blocking Therapy

Genetic predisposition in type 2 diabetes: A promising approach toward a personalized management of diabetes

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