Polygenic Risk Score Improves Cataract Prediction in East Asian Population

Hsu, Chih Chien; Chuang, Hao-Kai; Hsiao, Yu‐Jer; Teng, Yuan-Chi; Chiang, Pin-Hsuan; Wang, Yu-Jun; Lin, Ting‐Yi; Tsai, Ping-Hsing; Weng, Chang-Chi; Lin, Tai‐Chi; Hwang, De‐Kuang; Hsieh, Ai-Ru

doi:10.3390/biomedicines10081920

Cited by 3 publications

(1 citation statement)

References 60 publications

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“…The PCNT gene is highly expressed in heart, and is an integral component of the microtubule-organizing proteins, which exert compressive forces on cardiomyocytes that drive the development of cardiac disorders and T2DM ( 53 , 79 ). Interestingly, PCNT was also associated with cataract, indicating how microvascular and macrovascular complications tend to be strongly interrelated as damages of small vessels can ultimately results in heart disease manifestations in diabetes ( 80 , 81 ). The RILPL2 is highly expressed in lymphocytic cells and artery, and have been associated to obesity-related traits ( 43 , 70 ), including BMI and waist-to-hip ratio, as well as peripheral arterial disease ( 82 ).…”

Section: Resultsmentioning

confidence: 99%

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

et al. 2023

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BackgroundType 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies.MethodsThis cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina’s Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control.FindingsThe analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4).InterpretationWe have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina’s Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

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Section: Resultsmentioning

confidence: 99%

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

et al. 2023

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GWAS of cataract in Puerto Ricans identifies a novel large-effect variant in ITGA6

Shi

O’Connell

Hicks

et al. 2023

Preprint

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Cataract is a common cause of vision loss and affects millions of people worldwide. Genome-wide association studies (GWAS) and family studies of cataract have demonstrated a role for genetics in cataract susceptibility. However, most of these studies have been conducted in populations of European or Asian descent, leaving the genetic etiology of cataract among Hispanic/Latino (HL) populations unclear. Here we perform the first GWAS of cataract in a Puerto Rican population of research participants derived from the customer base of 23andMe, Inc. In our analysis with 3,060 self-reported cases and 41,890 controls, we found a novel association of large effect size with a rare coding variant in the ITGA6 gene (rs200560853, p-value=2.9*10^(-12), OR=12.7, 95% CI=[6.5, 24.7]). ITGA6 is part of the integrin alpha chain in the laminin receptor subfamily, and likely contributes to eye lens homeostasis, transparency, and cell survival. We found that this coding variant is associated with a 13.7 year earlier disease onset on average, as well as a 4.3-fold higher rate of cataract events in the Puerto Rican population. The variant has a minor allele frequency (MAF) of 0.089% in Puerto Rico and is extremely rare elsewhere in the world. Population genetic analyses showed that the variant is only found in individuals with ancestry from the Americas and countries bordering the Mediterranean Sea, suggesting a North African origin. Our discovery identifies a novel genetic risk factor for cataract in Puerto Ricans and highlights the importance of including underrepresented populations in genomics research to improve our understanding of disease in all populations.

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Polygenic Risk Scores and Genetically Complex Eye Disease

Le,

He,

MacGregor

2024

Annual Review of Vision Science

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The success of genome-wide association studies (GWASs) in uncovering genetic variants associated with complex eye diseases has paved the way for the development of risk prediction approaches based on disease genetics. Derived from GWAS data, polygenic risk scores (PRSs) have been emerging as a promising indicator of an individual's genetic liability to disease. In this review, we recap the current progress of PRS development and utility across a range of common eye diseases. While illustrating the prediction accuracy of PRSs and their valuable role in risk stratification for certain eye diseases, we also address PRSs’ uncertain implementation in clinical settings at this stage, particularly in circumstances where limited treatment options are available. Finally, we discuss obstacles in translating PRSs into practice, including barriers to clinical impact, issues when working with different ancestry groups, and communicating risk scores, as well as projections for future improvements.

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Polygenic Risk Score Improves Cataract Prediction in East Asian Population

Cited by 3 publications

References 60 publications

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

GWAS of cataract in Puerto Ricans identifies a novel large-effect variant in ITGA6

Polygenic Risk Scores and Genetically Complex Eye Disease

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