Author: "Tham, Y-C" - Searchworks@Jio Institute Digital Library Search Results

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1. Integrated image-based deep learning and language models for primary diabetes care

Author: Li, J, Guan, Z, Wang, J, Cheung, CY, Zheng, Y, Lim, L-L, Lim, CC, Ruamviboonsuk, P, Raman, R, Corsino, L, Echouffo-Tcheugui, JB, Luk, AOY, Chen, LJ, Sun, X, Hamzah, H, Wu, Q, Wang, X, Liu, R, Wang, YX, Chen, T, Zhang, X, Yang, X, Yin, J, Wan, J, Du, W, Quek, TC, Goh, JHL, Yang, D, Hu, X, Nguyen, TX, Szeto, SKH, Chotcomwongse, P, Malek, R, Normatova, N, Ibragimova, N, Srinivasan, R, Zhong, P, Huang, W, Deng, C, Ruan, L, Zhang, C, Zhou, Y, Wu, C, Dai, R, Koh, SWC, Abdullah, A, Hee, NKY, Tan, HC, Liew, ZH, Tien, CS-Y, Kao, SL, Lim, AYL, Mok, SF, Sun, L, Gu, J, Wu, L, Li, T, Cheng, D, Wang, Z, Qin, Y, Dai, L, Meng, Z, Shu, J, Lu, Y, Jiang, N, Hu, T, Huang, S, Huang, G, Yu, S, Liu, D, Ma, W, Guo, M, Guan, X, Bascaran, C, Cleland, CR, Bao, Y, Ekinci, EI, Jenkins, A, Chan, JCN, Bee, YM, Sivaprasad, S, Shaw, JE, Simo, R, Keane, PA, Cheng, C-Y, Tan, GSW, Jia, W, Tham, Y-C, Li, H, Sheng, B, Wong, TY, Li, J, Guan, Z, Wang, J, Cheung, CY, Zheng, Y, Lim, L-L, Lim, CC, Ruamviboonsuk, P, Raman, R, Corsino, L, Echouffo-Tcheugui, JB, Luk, AOY, Chen, LJ, Sun, X, Hamzah, H, Wu, Q, Wang, X, Liu, R, Wang, YX, Chen, T, Zhang, X, Yang, X, Yin, J, Wan, J, Du, W, Quek, TC, Goh, JHL, Yang, D, Hu, X, Nguyen, TX, Szeto, SKH, Chotcomwongse, P, Malek, R, Normatova, N, Ibragimova, N, Srinivasan, R, Zhong, P, Huang, W, Deng, C, Ruan, L, Zhang, C, Zhou, Y, Wu, C, Dai, R, Koh, SWC, Abdullah, A, Hee, NKY, Tan, HC, Liew, ZH, Tien, CS-Y, Kao, SL, Lim, AYL, Mok, SF, Sun, L, Gu, J, Wu, L, Li, T, Cheng, D, Wang, Z, Qin, Y, Dai, L, Meng, Z, Shu, J, Lu, Y, Jiang, N, Hu, T, Huang, S, Huang, G, Yu, S, Liu, D, Ma, W, Guo, M, Guan, X, Bascaran, C, Cleland, CR, Bao, Y, Ekinci, EI, Jenkins, A, Chan, JCN, Bee, YM, Sivaprasad, S, Shaw, JE, Simo, R, Keane, PA, Cheng, C-Y, Tan, GSW, Jia, W, Tham, Y-C, Li, H, Sheng, B, and Wong, TY
Abstract: Primary diabetes care and diabetic retinopathy (DR) screening persist as major public health challenges due to a shortage of trained primary care physicians (PCPs), particularly in low-resource settings. Here, to bridge the gaps, we developed an integrated image-language system (DeepDR-LLM), combining a large language model (LLM module) and image-based deep learning (DeepDR-Transformer), to provide individualized diabetes management recommendations to PCPs. In a retrospective evaluation, the LLM module demonstrated comparable performance to PCPs and endocrinology residents when tested in English and outperformed PCPs and had comparable performance to endocrinology residents in Chinese. For identifying referable DR, the average PCP's accuracy was 81.0% unassisted and 92.3% assisted by DeepDR-Transformer. Furthermore, we performed a single-center real-world prospective study, deploying DeepDR-LLM. We compared diabetes management adherence of patients under the unassisted PCP arm (n = 397) with those under the PCP+DeepDR-LLM arm (n = 372). Patients with newly diagnosed diabetes in the PCP+DeepDR-LLM arm showed better self-management behaviors throughout follow-up (P < 0.05). For patients with referral DR, those in the PCP+DeepDR-LLM arm were more likely to adhere to DR referrals (P < 0.01). Additionally, DeepDR-LLM deployment improved the quality and empathy level of management recommendations. Given its multifaceted performance, DeepDR-LLM holds promise as a digital solution for enhancing primary diabetes care and DR screening.
Published: 2024

2. A deep-learning-based retinal cardiovascular disease biomarker and risk of stroke, myocardial infarction, atrial fibrillation, and heart failure in the UK Biobank

Author: Lee, C J, primary, Rim, T H, additional, Kang, H G, additional, Lee, G, additional, Yu, M, additional, Tham, Y C, additional, Wong, T Y, additional, Cheng, C Y, additional, Kim, S S, additional, Kang, S M, additional, and Park, S, additional
Published: 2023
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3. Detecting visually significant cataract using retinal photograph-based deep learning

Author: Tham, Y-C, Goh, JHL, Anees, A, Lei, X, Rim, TH, Chee, M-L, Wang, YX, Jonas, JB, Thakur, S, Teo, ZL, Cheung, N, Hamzah, H, Tan, GSW, Husain, R, Sabanayagam, C, Wang, JJ, Chen, Q, Lu, Z, Keenan, TD, Chew, EY, Tan, AG, Mitchell, P, Goh, RSM, Xu, X, Liu, Y, Wong, TY, Cheng, C-Y, Tham, Y-C, Goh, JHL, Anees, A, Lei, X, Rim, TH, Chee, M-L, Wang, YX, Jonas, JB, Thakur, S, Teo, ZL, Cheung, N, Hamzah, H, Tan, GSW, Husain, R, Sabanayagam, C, Wang, JJ, Chen, Q, Lu, Z, Keenan, TD, Chew, EY, Tan, AG, Mitchell, P, Goh, RSM, Xu, X, Liu, Y, Wong, TY, and Cheng, C-Y
Abstract: Age-related cataracts are the leading cause of visual impairment among older adults. Many significant cases remain undiagnosed or neglected in communities, due to limited availability or accessibility to cataract screening. In the present study, we report the development and validation of a retinal photograph-based, deep-learning algorithm for automated detection of visually significant cataracts, using more than 25,000 images from population-based studies. In the internal test set, the area under the receiver operating characteristic curve (AUROC) was 96.6%. External testing performed across three studies showed AUROCs of 91.6-96.5%. In a separate test set of 186 eyes, we further compared the algorithm's performance with 4 ophthalmologists' evaluations. The algorithm performed comparably, if not being slightly more superior (sensitivity of 93.3% versus 51.7-96.6% by ophthalmologists and specificity of 99.0% versus 90.7-97.9% by ophthalmologists). Our findings show the potential of a retinal photograph-based screening tool for visually significant cataracts among older adults, providing more appropriate referrals to tertiary eye centers.
Published: 2022

4. New digital models of care in ophthalmology, during and beyond the COVID-19 pandemic.

Author: Tham, Y-C, Husain, R, Teo, KYC, Tan, ACS, Chew, ACY, Ting, DS, Cheng, C-Y, Tan, GSW, Wong, TY, Tham, Y-C, Husain, R, Teo, KYC, Tan, ACS, Chew, ACY, Ting, DS, Cheng, C-Y, Tan, GSW, and Wong, TY
Abstract: COVID-19 has led to massive disruptions in societal, economic and healthcare systems globally. While COVID-19 has sparked a surge and expansion of new digital business models in different industries, healthcare has been slower to adapt to digital solutions. The majority of ophthalmology clinical practices are still operating through a traditional model of 'brick-and-mortar' facilities and 'face-to-face' patient-physician interaction. In the current climate of COVID-19, there is a need to fuel implementation of digital health models for ophthalmology. In this article, we highlight the current limitations in traditional clinical models as we confront COVID-19, review the current lack of digital initiatives in ophthalmology sphere despite the presence of COVID-19, propose new digital models of care for ophthalmology and discuss potential barriers that need to be considered for sustainable transformation to take place.
Published: 2022

5. Deep learning algorithms for automatic detection of pterygium using anterior segment photographs from slit-lamp and hand-held cameras.

Author: Fang, X, Deshmukh, M, Chee, ML, Soh, Z-D, Teo, ZL, Thakur, S, Goh, JHL, Liu, Y-C, Husain, R, Mehta, JS, Wong, TY, Cheng, C-Y, Rim, TH, Tham, Y-C, Fang, X, Deshmukh, M, Chee, ML, Soh, Z-D, Teo, ZL, Thakur, S, Goh, JHL, Liu, Y-C, Husain, R, Mehta, JS, Wong, TY, Cheng, C-Y, Rim, TH, and Tham, Y-C
Abstract: BACKGROUND/AIMS: To evaluate the performances of deep learning (DL) algorithms for detection of presence and extent pterygium, based on colour anterior segment photographs (ASPs) taken from slit-lamp and hand-held cameras. METHODS: Referable pterygium was defined as having extension towards the cornea from the limbus of >2.50 mm or base width at the limbus of >5.00 mm. 2503 images from the Singapore Epidemiology of Eye Diseases (SEED) study were used as the development set. Algorithms were validated on an internal set from the SEED cohort (629 images (55.3% pterygium, 8.4% referable pterygium)), and tested on two external clinic-based sets (set 1 with 2610 images (2.8% pterygium, 0.7% referable pterygium, from slit-lamp ASP); and set 2 with 3701 images, 2.5% pterygium, 0.9% referable pterygium, from hand-held ASP). RESULTS: The algorithm's area under the receiver operating characteristic curve (AUROC) for detection of any pterygium was 99.5%(sensitivity=98.6%; specificity=99.0%) in internal test set, 99.1% (sensitivity=95.9%, specificity=98.5%) in external test set 1 and 99.7% (sensitivity=100.0%; specificity=88.3%) in external test set 2. For referable pterygium, the algorithm's AUROC was 98.5% (sensitivity=94.0%; specificity=95.3%) in internal test set, 99.7% (sensitivity=87.2%; specificity=99.4%) in external set 1 and 99.0% (sensitivity=94.3%; specificity=98.0%) in external set 2. CONCLUSION: DL algorithms based on ASPs can detect presence of and referable-level pterygium with optimal sensitivity and specificity. These algorithms, particularly if used with a handheld camera, may potentially be used as a simple screening tool for detection of referable pterygium. Further validation in community setting is warranted. SYNOPSIS/PRECIS: DL algorithms based on ASPs can detect presence of and referable-level pterygium optimally, and may be used as a simple screening tool for the detection of referable pterygium in community screenings.
Published: 2022

6. Relationships between Lipid-Related Metabolites and Age-Related Macular Degeneration Vary with Complement Genotype.

Author: Sim, RZH, Tham, Y-C, Betzler, BK, Zhou, L, Wang, X, Sabanayagam, C, Cheung, GCM, Wong, TY, Cheng, C-Y, Nusinovici, S, Sim, RZH, Tham, Y-C, Betzler, BK, Zhou, L, Wang, X, Sabanayagam, C, Cheung, GCM, Wong, TY, Cheng, C-Y, and Nusinovici, S
Abstract: OBJECTIVE: Lipid dysregulation and complement system (CS) activation are 2 important pathophysiology pathways for age-related macular degeneration (AMD). We hypothesized that the relationship between lipids and AMD may also differ according to CS genotype profile. Thus, the objective was to investigate the relationships between lipid-related metabolites and AMD according to CS genotypes. DESIGN: Population-based cross-sectional study. PARTICIPANTS: A total of 6947 participants from Singapore Epidemiology of Eye Diseases study with complete relevant data were included. METHODS: We investigated a total of 32 blood lipid-related metabolites from nuclear magnetic resonance metabolomics data including lipoproteins and their subclasses, cholesterols, glycerides, and phospholipids, as well as 4 CS single nucleotide polymorphisms (SNPs): rs10922109 (complement factor H), rs10033900 (complement factor I), rs116503776 (C2-CFB-SKIV2L), and rs2230199 (C3). We first investigated the associations between AMD and the 32 lipid-related metabolites using multivariable logistic regression models. Then, to investigate whether the effect of lipid-related metabolites on AMD differ according to the CS SNPs, we tested the possible interactions between the CS SNPs and the lipid-related metabolites. MAIN OUTCOME MEASURES: Age-related macular degeneration was defined using the Wisconsin grading system. RESULTS: Among the 6947 participants, the prevalence of AMD was 6.1%, and the mean age was 58.3 years. First, higher levels of cholesterol in high-density lipoprotein (HDL) and medium and large HDL particles were associated with an increased risk of AMD, and higher levels of serum total triglycerides (TG) and several very-low-density lipoprotein subclass particles were associated with a decreased risk of AMD. Second, these lipids had significant interaction effects on AMD with 2 CS SNPs: rs2230199 and rs116503776 (after correction for multiple testing). For rs2230199, in individuals without ris
Published: 2022

7. Author Correction: Detecting visually significant cataract using retinal photograph-based deep learning.

Author: Tham, Y-C, Goh, JHL, Anees, A, Lei, X, Rim, TH, Chee, M-L, Wang, YX, Jonas, JB, Thakur, S, Teo, ZL, Cheung, N, Hamzah, H, Tan, GSW, Husain, R, Sabanayagam, C, Wang, JJ, Chen, Q, Lu, Z, Keenan, TD, Chew, EY, Tan, AG, Mitchell, P, Goh, RSM, Xu, X, Liu, Y, Wong, TY, Cheng, C-Y, Tham, Y-C, Goh, JHL, Anees, A, Lei, X, Rim, TH, Chee, M-L, Wang, YX, Jonas, JB, Thakur, S, Teo, ZL, Cheung, N, Hamzah, H, Tan, GSW, Husain, R, Sabanayagam, C, Wang, JJ, Chen, Q, Lu, Z, Keenan, TD, Chew, EY, Tan, AG, Mitchell, P, Goh, RSM, Xu, X, Liu, Y, Wong, TY, and Cheng, C-Y
Published: 2022

8. Considerations for Artificial Intelligence Real-World Implementation in Ophthalmology: Providers' and Patients' Perspectives.

Author: Tseng, RMWW, Gunasekeran, DV, Tan, SSH, Rim, TH, Lum, E, Tan, GSW, Wong, TY, Tham, Y-C, Tseng, RMWW, Gunasekeran, DV, Tan, SSH, Rim, TH, Lum, E, Tan, GSW, Wong, TY, and Tham, Y-C
Abstract: Artificial Intelligence (AI), in particular deep learning, has made waves in the health care industry, with several prominent examples shown in ophthalmology. Despite the burgeoning reports on the development of new AI algorithms for detection and management of various eye diseases, few have reached the stage of regulatory approval for real-world implementation. To better enable real-world translation of AI systems, it is important to understand the demands, needs, and concerns of both health care professionals and patients, as providers and recipients of clinical care are impacted by these solutions. This review outlines the advantages and concerns of incorporating AI in ophthalmology care delivery, from both the providers' and patients' perspectives, and the key enablers for seamless transition to real-world implementation.
Published: 2021

9. COVID-19 awareness, knowledge and perception towards digital health in an urban multi-ethnic Asian population.

Author: Teo, CL, Chee, ML, Koh, KH, Tseng, RMWW, Majithia, S, Thakur, S, Gunasekeran, DV, Nusinovici, S, Sabanayagam, C, Wong, TY, Tham, Y-C, Cheng, C-Y, Teo, CL, Chee, ML, Koh, KH, Tseng, RMWW, Majithia, S, Thakur, S, Gunasekeran, DV, Nusinovici, S, Sabanayagam, C, Wong, TY, Tham, Y-C, and Cheng, C-Y
Abstract: This study aimed to determine COVID-19-related awareness, knowledge, impact and preparedness among elderly Asians; and to evaluate their acceptance towards digital health services amidst the pandemic. 523 participants (177 Malays, 171 Indians, 175 Chinese) were recruited and underwent standardised phone interview during Singapore's lockdown period (07 April till 01 June 2020). Multivariable logistic regression models were performed to evaluate the associations between demographic, socio-economic, lifestyle, and systemic factors, with COVID-19 awareness, knowledge, preparedness, well-being and digital health service acceptance. The average perception score on the seriousness of COVID-19 was 7.6 ± 2.4 (out of 10). 75.5% of participants were aware that COVID-19 carriers can be asymptomatic. Nearly all (≥ 90%) were aware of major prevention methods for COVID-19 (i.e. wearing of mask, social distancing). 66.2% felt prepared for the pandemic, and 86.8% felt confident with government's handling and measures. 78.4% felt their daily routine was impacted. 98.1% reported no prior experience in using digital health services, but 52.2% felt these services would be helpful to reduce non-essential contact. 77.8% were uncomfortable with artificial intelligence software interpreting their medical results. In multivariable analyses, Chinese participants felt less prepared, and more likely felt impacted by COVID-19. Older and lower income participants were less likely to use digital health services. In conclusion, we observed a high level of awareness and knowledge on COVID-19. However, acceptance towards digital health service was low. These findings are valuable for examining the effectiveness of COVID-19 communication in Singapore, and the remaining gaps in digital health adoption among elderly.
Published: 2021

10. Ethnic differences in the incidence of pterygium in a multi-ethnic Asian population: the Singapore Epidemiology of Eye Diseases Study.

Author: Fang, XL, Chong, CCY, Thakur, S, Da Soh, Z, Teo, ZL, Majithia, S, Lim, ZW, Rim, TH, Sabanayagam, C, Wong, TY, Cheng, C-Y, Tham, Y-C, Fang, XL, Chong, CCY, Thakur, S, Da Soh, Z, Teo, ZL, Majithia, S, Lim, ZW, Rim, TH, Sabanayagam, C, Wong, TY, Cheng, C-Y, and Tham, Y-C
Abstract: We evaluated the 6-year incidence and risk factors of pterygium in a multi-ethnic Asian population. Participants who attended the baseline visit of the Singapore Epidemiology of Eye Diseases Study (year 2004-2011) and returned six years later, were included in this study. Pterygium was diagnosed based on anterior segment photographs. Incident pterygium was defined as presence of pterygium at 6-year follow-up in either eye, among individuals without pterygium at baseline. Multivariable logistic regression models were used to determine factors associated with incident pterygium, adjusting for baseline age, gender, ethnicity, body mass index, occupation type, educational level, income status, smoking, alcohol consumption, presence of hypertension, diabetes and hyperlipidemia. The overall age-adjusted 6-year incidence of pterygium was 1.2% (95% confidence interval [CI] 1.0-1.6%); with Chinese (1.9%; 95% CI 1.4%-2.5%) having the highest incidence rate followed by Malays (1.4%; 95% CI 0.9%-2.1%) and Indians (0.3%; 95% CI 0.3-0.7%). In multivariable analysis, Chinese (compared with Indians; odds ratio [OR] = 4.21; 95% CI 2.12-9.35) and Malays (OR 3.22; 95% CI 1.52-7.45), male (OR 2.13; 95% CI 1.26-3.63), outdoor occupation (OR 2.33; 95% CI 1.16-4.38), and smoking (OR 0.41; 95% CI 0.16-0.87) were significantly associated with incident pterygium. Findings from this multi-ethnic Asian population provide useful information in identifying at-risk individuals for pterygium.
Published: 2021

11. Digital health during COVID-19: lessons from operationalising new models of care in ophthalmology.

Author: Gunasekeran, DV, Tham, Y-C, Ting, DSW, Tan, GSW, Wong, TY, Gunasekeran, DV, Tham, Y-C, Ting, DSW, Tan, GSW, and Wong, TY
Abstract: The COVID-19 pandemic has resulted in massive disruptions within health care, both directly as a result of the infectious disease outbreak, and indirectly because of public health measures to mitigate against transmission. This disruption has caused rapid dynamic fluctuations in demand, capacity, and even contextual aspects of health care. Therefore, the traditional face-to-face patient-physician care model has had to be re-examined in many countries, with digital technology and new models of care being rapidly deployed to meet the various challenges of the pandemic. This Viewpoint highlights new models in ophthalmology that have adapted to incorporate digital health solutions such as telehealth, artificial intelligence decision support for triaging and clinical care, and home monitoring. These models can be operationalised for different clinical applications based on the technology, clinical need, demand from patients, and manpower availability, ranging from out-of-hospital models including the hub-and-spoke pre-hospital model, to front-line models such as the inflow funnel model and monitoring models such as the so-called lighthouse model for provider-led monitoring. Lessons learnt from operationalising these models for ophthalmology in the context of COVID-19 are discussed, along with their relevance for other specialty domains.
Published: 2021

12. Retinal photograph-based deep learning algorithms for myopia and a blockchain platform to facilitate artificial intelligence medical research: a retrospective multicohort study.

Author: Tan, T-E, Anees, A, Chen, C, Li, S, Xu, X, Li, Z, Xiao, Z, Yang, Y, Lei, X, Ang, M, Chia, A, Lee, SY, Wong, EYM, Yeo, IYS, Wong, YL, Hoang, QV, Wang, YX, Bikbov, MM, Nangia, V, Jonas, JB, Chen, Y-P, Wu, W-C, Ohno-Matsui, K, Rim, TH, Tham, Y-C, Goh, RSM, Lin, H, Liu, H, Wang, N, Yu, W, Tan, DTH, Schmetterer, L, Cheng, C-Y, Chen, Y, Wong, CW, Cheung, GCM, Saw, S-M, Wong, TY, Liu, Y, Ting, DSW, Tan, T-E, Anees, A, Chen, C, Li, S, Xu, X, Li, Z, Xiao, Z, Yang, Y, Lei, X, Ang, M, Chia, A, Lee, SY, Wong, EYM, Yeo, IYS, Wong, YL, Hoang, QV, Wang, YX, Bikbov, MM, Nangia, V, Jonas, JB, Chen, Y-P, Wu, W-C, Ohno-Matsui, K, Rim, TH, Tham, Y-C, Goh, RSM, Lin, H, Liu, H, Wang, N, Yu, W, Tan, DTH, Schmetterer, L, Cheng, C-Y, Chen, Y, Wong, CW, Cheung, GCM, Saw, S-M, Wong, TY, Liu, Y, and Ting, DSW
Abstract: BACKGROUND: By 2050, almost 5 billion people globally are projected to have myopia, of whom 20% are likely to have high myopia with clinically significant risk of sight-threatening complications such as myopic macular degeneration. These are diagnoses that typically require specialist assessment or measurement with multiple unconnected pieces of equipment. Artificial intelligence (AI) approaches might be effective for risk stratification and to identify individuals at highest risk of visual loss. However, unresolved challenges for AI medical studies remain, including paucity of transparency, auditability, and traceability. METHODS: In this retrospective multicohort study, we developed and tested retinal photograph-based deep learning algorithms for detection of myopic macular degeneration and high myopia, using a total of 226 686 retinal images. First we trained and internally validated the algorithms on datasets from Singapore, and then externally tested them on datasets from China, Taiwan, India, Russia, and the UK. We also compared the performance of the deep learning algorithms against six human experts in the grading of a randomly selected dataset of 400 images from the external datasets. As proof of concept, we used a blockchain-based AI platform to demonstrate the real-world application of secure data transfer, model transfer, and model testing across three sites in Singapore and China. FINDINGS: The deep learning algorithms showed robust diagnostic performance with areas under the receiver operating characteristic curves [AUC] of 0·969 (95% CI 0·959-0·977) or higher for myopic macular degeneration and 0·913 (0·906-0·920) or higher for high myopia across the external testing datasets with available data. In the randomly selected dataset, the deep learning algorithms outperformed all six expert graders in detection of each condition (AUC of 0·978 [0·957-0·994] for myopic macular degeneration and 0·973 [0·941-0·995] for high myopia). We also successfully used b
Published: 2021

13. Referral for disease-related visual impairment using retinal photograph-based deep learning: a proof-of-concept, model development study

Author: Tham, Y-C, Anees, A, Zhang, L, Goh, JHL, Rim, TH, Nusinovici, S, Hamzah, H, Chee, M-L, Tjio, G, Li, S, Xu, X, Goh, R, Tang, F, Cheung, CY-L, Wang, YX, Nangia, V, Jonas, JB, Gopinath, B, Mitchell, P, Husain, R, Lamoureux, E, Sabanayagam, C, Wang, JJ, Aung, T, Liu, Y, Wong, TY, Cheng, C-Y, Tham, Y-C, Anees, A, Zhang, L, Goh, JHL, Rim, TH, Nusinovici, S, Hamzah, H, Chee, M-L, Tjio, G, Li, S, Xu, X, Goh, R, Tang, F, Cheung, CY-L, Wang, YX, Nangia, V, Jonas, JB, Gopinath, B, Mitchell, P, Husain, R, Lamoureux, E, Sabanayagam, C, Wang, JJ, Aung, T, Liu, Y, Wong, TY, and Cheng, C-Y
Abstract: BACKGROUND: In current approaches to vision screening in the community, a simple and efficient process is needed to identify individuals who should be referred to tertiary eye care centres for vision loss related to eye diseases. The emergence of deep learning technology offers new opportunities to revolutionise this clinical referral pathway. We aimed to assess the performance of a newly developed deep learning algorithm for detection of disease-related visual impairment. METHODS: In this proof-of-concept study, using retinal fundus images from 15 175 eyes with complete data related to best-corrected visual acuity or pinhole visual acuity from the Singapore Epidemiology of Eye Diseases Study, we first developed a single-modality deep learning algorithm based on retinal photographs alone for detection of any disease-related visual impairment (defined as eyes from patients with major eye diseases and best-corrected visual acuity of <20/40), and moderate or worse disease-related visual impairment (eyes with disease and best-corrected visual acuity of <20/60). After development of the algorithm, we tested it internally, using a new set of 3803 eyes from the Singapore Epidemiology of Eye Diseases Study. We then tested it externally using three population-based studies (the Beijing Eye study [6239 eyes], Central India Eye and Medical study [6526 eyes], and Blue Mountains Eye Study [2002 eyes]), and two clinical studies (the Chinese University of Hong Kong's Sight Threatening Diabetic Retinopathy study [971 eyes] and the Outram Polyclinic Study [1225 eyes]). The algorithm's performance in each dataset was assessed on the basis of the area under the receiver operating characteristic curve (AUC). FINDINGS: In the internal test dataset, the AUC for detection of any disease-related visual impairment was 94·2% (95% CI 93·0-95·3; sensitivity 90·7% [87·0-93·6]; specificity 86·8% [85·6-87·9]). The AUC for moderate or worse disease-related visual impairment was 93·9% (95% CI 92·2
Published: 2021

14. Gender Prediction for a Multiethnic Population via Deep Learning Across Different Retinal Fundus Photograph Fields: Retrospective Cross-sectional Study.

Author: Betzler, BK, Yang, HHS, Thakur, S, Yu, M, Quek, TC, Soh, ZD, Lee, G, Tham, Y-C, Wong, TY, Rim, TH, Cheng, C-Y, Betzler, BK, Yang, HHS, Thakur, S, Yu, M, Quek, TC, Soh, ZD, Lee, G, Tham, Y-C, Wong, TY, Rim, TH, and Cheng, C-Y
Abstract: BACKGROUND: Deep learning algorithms have been built for the detection of systemic and eye diseases based on fundus photographs. The retina possesses features that can be affected by gender differences, and the extent to which these features are captured via photography differs depending on the retinal image field. OBJECTIVE: We aimed to compare deep learning algorithms' performance in predicting gender based on different fields of fundus photographs (optic disc-centered, macula-centered, and peripheral fields). METHODS: This retrospective cross-sectional study included 172,170 fundus photographs of 9956 adults aged ≥40 years from the Singapore Epidemiology of Eye Diseases Study. Optic disc-centered, macula-centered, and peripheral field fundus images were included in this study as input data for a deep learning model for gender prediction. Performance was estimated at the individual level and image level. Receiver operating characteristic curves for binary classification were calculated. RESULTS: The deep learning algorithms predicted gender with an area under the receiver operating characteristic curve (AUC) of 0.94 at the individual level and an AUC of 0.87 at the image level. Across the three image field types, the best performance was seen when using optic disc-centered field images (younger subgroups: AUC=0.91; older subgroups: AUC=0.86), and algorithms that used peripheral field images had the lowest performance (younger subgroups: AUC=0.85; older subgroups: AUC=0.76). Across the three ethnic subgroups, algorithm performance was lowest in the Indian subgroup (AUC=0.88) compared to that in the Malay (AUC=0.91) and Chinese (AUC=0.91) subgroups when the algorithms were tested on optic disc-centered images. Algorithms' performance in gender prediction at the image level was better in younger subgroups (aged <65 years; AUC=0.89) than in older subgroups (aged ≥65 years; AUC=0.82). CONCLUSIONS: We confirmed that gender among the Asian population can be predicted wit
Published: 2021

15. Applications of digital health for public health responses to COVID-19: a systematic scoping review of artificial intelligence, telehealth and related technologies.

Author: Gunasekeran, DV, Tseng, RMWW, Tham, Y-C, Wong, TY, Gunasekeran, DV, Tseng, RMWW, Tham, Y-C, and Wong, TY
Abstract: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed healthcare services, faced with the twin challenges in acutely meeting the medical needs of patients with COVID-19 while continuing essential services for non-COVID-19 illnesses. The need to re-invent, re-organize and transform healthcare and co-ordinate clinical services at a population level is urgent as countries that controlled initial outbreaks start to experience resurgences. A wide range of digital health solutions have been proposed, although the extent of successful real-world applications of these technologies is unclear. This study aims to review applications of artificial intelligence (AI), telehealth, and other relevant digital health solutions for public health responses in the healthcare operating environment amidst the COVID-19 pandemic. A systematic scoping review was performed to identify potentially relevant reports. Key findings include a large body of evidence for various clinical and operational applications of telehealth (40.1%, n = 99/247). Although a large quantity of reports investigated applications of artificial intelligence (AI) (44.9%, n = 111/247) and big data analytics (36.0%, n = 89/247), weaknesses in study design limit generalizability and translation, highlighting the need for more pragmatic real-world investigations. There were also few descriptions of applications for the internet of things (IoT) (2.0%, n = 5/247), digital platforms for communication (DC) (10.9%, 27/247), digital solutions for data management (DM) (1.6%, n = 4/247), and digital structural screening (DS) (8.9%, n = 22/247); representing gaps and opportunities for digital public health. Finally, the performance of digital health technology for operational applications related to population surveillance and points of entry have not been adequately evaluated.
Published: 2021

16. Deep-learning-based cardiovascular risk stratification using coronary artery calcium scores predicted from retinal photographs.

Author: Rim, TH, Lee, CJ, Tham, Y-C, Cheung, N, Yu, M, Lee, G, Kim, Y, Ting, DSW, Chong, CCY, Choi, YS, Yoo, TK, Ryu, IH, Baik, SJ, Kim, YA, Kim, SK, Lee, S-H, Lee, BK, Kang, S-M, Wong, EYM, Kim, HC, Kim, SS, Park, S, Cheng, C-Y, Wong, TY, Rim, TH, Lee, CJ, Tham, Y-C, Cheung, N, Yu, M, Lee, G, Kim, Y, Ting, DSW, Chong, CCY, Choi, YS, Yoo, TK, Ryu, IH, Baik, SJ, Kim, YA, Kim, SK, Lee, S-H, Lee, BK, Kang, S-M, Wong, EYM, Kim, HC, Kim, SS, Park, S, Cheng, C-Y, and Wong, TY
Abstract: BACKGROUND: Coronary artery calcium (CAC) score is a clinically validated marker of cardiovascular disease risk. We developed and validated a novel cardiovascular risk stratification system based on deep-learning-predicted CAC from retinal photographs. METHODS: We used 216 152 retinal photographs from five datasets from South Korea, Singapore, and the UK to train and validate the algorithms. First, using one dataset from a South Korean health-screening centre, we trained a deep-learning algorithm to predict the probability of the presence of CAC (ie, deep-learning retinal CAC score, RetiCAC). We stratified RetiCAC scores into tertiles and used Cox proportional hazards models to evaluate the ability of RetiCAC to predict cardiovascular events based on external test sets from South Korea, Singapore, and the UK Biobank. We evaluated the incremental values of RetiCAC when added to the Pooled Cohort Equation (PCE) for participants in the UK Biobank. FINDINGS: RetiCAC outperformed all single clinical parameter models in predicting the presence of CAC (area under the receiver operating characteristic curve of 0·742, 95% CI 0·732-0·753). Among the 527 participants in the South Korean clinical cohort, 33 (6·3%) had cardiovascular events during the 5-year follow-up. When compared with the current CAC risk stratification (0, >0-100, and >100), the three-strata RetiCAC showed comparable prognostic performance with a concordance index of 0·71. In the Singapore population-based cohort (n=8551), 310 (3·6%) participants had fatal cardiovascular events over 10 years, and the three-strata RetiCAC was significantly associated with increased risk of fatal cardiovascular events (hazard ratio [HR] trend 1·33, 95% CI 1·04-1·71). In the UK Biobank (n=47 679), 337 (0·7%) participants had fatal cardiovascular events over 10 years. When added to the PCE, the three-strata RetiCAC improved cardiovascular risk stratification in the intermediate-risk group (HR trend 1·28, 95% CI 1·07-1·54) and bo
Published: 2021

17. A Peer-to-Peer Live-Streaming Intervention for Children During COVID-19 Homeschooling to Promote Physical Activity and Reduce Anxiety and Eye Strain: Cluster Randomized Controlled Trial

Author: Zheng, Y, Wang, W, Zhong, Y, Wu, F, Zhu, Z, Tham, Y-C, Lamoureux, E, Xiao, L, Zhu, E, Liu, H, Jin, L, Liang, L, Luo, L, He, M, Morgan, I, Congdon, N, Liu, Y, Zheng, Y, Wang, W, Zhong, Y, Wu, F, Zhu, Z, Tham, Y-C, Lamoureux, E, Xiao, L, Zhu, E, Liu, H, Jin, L, Liang, L, Luo, L, He, M, Morgan, I, Congdon, N, and Liu, Y
Abstract: BACKGROUND: The COVID-19 pandemic has led to worldwide school closures, with millions of children confined to online learning at home. As a result, children may be susceptible to anxiety and digital eye strain, highlighting a need for population interventions. OBJECTIVE: The objective of our study was to investigate whether a digital behavior change intervention aimed at promoting physical activity could reduce children's anxiety and digital eye strain while undergoing prolonged homeschooling during the COVID-19 pandemic. METHODS: In this cluster randomized controlled trial, homeschooled grade 7 students at 12 middle schools in southern China were recruited through local schools and randomly assigned by the school to receive (1:1 allocation): (1) health education information promoting exercise and ocular relaxation, and access to a digital behavior change intervention, with live streaming and peer sharing of promoted activities (intervention), or (2) health education information only (control). The primary outcome was change in self-reported anxiety score. Secondary outcomes included change in self-reported eye strain and sleep quality. RESULTS: On March 16, 2020, 1009 children were evaluated, and 954 (94.5%) eligible children of consenting families were included in the intention-to-treat analysis. Children in the intervention (n=485, 6 schools) and control (n=469, 6 schools) groups were aged 13.5 (SD 0.5) years, and 52.3% (n=499) were male. The assigned interventions were completed by 896 children (intervention: n=467, 96.3%; control: n=429, 91.5%). The 2-week change in square-root-transformed self-reported anxiety scores was greater in the intervention (-0.23, 95% CI -0.27 to -0.20) vs control group (0.12, 95% CI 0.09-0.16; unadjusted difference -0.36, 95% CI -0.63 to -0.08; P=.02). There was a significant reduction in square-root-transformed eye strain in the intervention group (-0.08, 95% CI -0.10 to 0.06) compared to controls (0.07, 95% CI 0.05-0.09; difference
Published: 2021

18. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Author: Yonova-Doing, E. (Ekaterina), Zhao, W. (Wanting), Igo Jr., R.P. (Robert), Wang, C. (Chunliang), Sundaresan, P. (Periasamy), Lee, K.E. (Kristine), Jun, G.R. (Gyungah R.), Alves, A.C. (Alexessander Couto), Chai, X. (Xiaoran), Chan, A.S.Y. (Anita S. Y.), Lee, M.C. (Mei Chin), Fong, A. (Allan), Tan, A.G. (Ava G.), Khor, C.C., Chew, E.Y. (Emily Y.), Hysi, P.G. (Pirro G.), Fan, Q. (Qiao), Chua, J. (Jacqueline), Chung, J. (Jaeyoon), Liao, J. (Jiemin), Colijn, J.M. (Johanna), Burdon, K.P. (Kathryn P.), Fritsche, L.G. (Lars), Swift, M.K. (Maria K.), Hilmy, M.H. (Maryam H.), Chee, M.L. (Miao Ling), Tedja, M. (Milly), Bonnemaijer, P.W.M. (Pieter), Gupta, P. (Preeti), Tan, Q.S. (Queenie S.), Li, Z. (Zheng), Vithana, E.N. (Eranga), Ravindran, R.D. (Ravilla D.), Chee, S.-P. (Soon-Phaik), Shi, Y. (Yuan), Liu, W. (Wenting), Su, X. (Xinyi), Sim, X. (Xueling), Shen, Y. (Yang), Wang, Y.X. (Ya Xing), Li, H. (Hengtong), Tham, Y.-C. (Yih-Chung), Teo, Y.Y. (Yik Ying), Aung, T. (Tin), Small, K.S. (Kerrin S.), Mitchell, P. (Paul), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fletcher, A. (Astrid), Klaver, C.C.W. (Caroline), Klein, B.E.K. (Barbara E. K.), Wang, J.J. (Jie Jin), Iyengar, S.K. (Sudha K.), Hammond, C.J. (Christopher J.), Cheng, C.-Y. (Ching-Yu), Yonova-Doing, E. (Ekaterina), Zhao, W. (Wanting), Igo Jr., R.P. (Robert), Wang, C. (Chunliang), Sundaresan, P. (Periasamy), Lee, K.E. (Kristine), Jun, G.R. (Gyungah R.), Alves, A.C. (Alexessander Couto), Chai, X. (Xiaoran), Chan, A.S.Y. (Anita S. Y.), Lee, M.C. (Mei Chin), Fong, A. (Allan), Tan, A.G. (Ava G.), Khor, C.C., Chew, E.Y. (Emily Y.), Hysi, P.G. (Pirro G.), Fan, Q. (Qiao), Chua, J. (Jacqueline), Chung, J. (Jaeyoon), Liao, J. (Jiemin), Colijn, J.M. (Johanna), Burdon, K.P. (Kathryn P.), Fritsche, L.G. (Lars), Swift, M.K. (Maria K.), Hilmy, M.H. (Maryam H.), Chee, M.L. (Miao Ling), Tedja, M. (Milly), Bonnemaijer, P.W.M. (Pieter), Gupta, P. (Preeti), Tan, Q.S. (Queenie S.), Li, Z. (Zheng), Vithana, E.N. (Eranga), Ravindran, R.D. (Ravilla D.), Chee, S.-P. (Soon-Phaik), Shi, Y. (Yuan), Liu, W. (Wenting), Su, X. (Xinyi), Sim, X. (Xueling), Shen, Y. (Yang), Wang, Y.X. (Ya Xing), Li, H. (Hengtong), Tham, Y.-C. (Yih-Chung), Teo, Y.Y. (Yik Ying), Aung, T. (Tin), Small, K.S. (Kerrin S.), Mitchell, P. (Paul), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fletcher, A. (Astrid), Klaver, C.C.W. (Caroline), Klein, B.E.K. (Barbara E. K.), Wang, J.J. (Jie Jin), Iyengar, S.K. (Sudha K.), Hammond, C.J. (Christopher J.), and Cheng, C.-Y. (Ching-Yu)
Abstract: Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10
Published: 2020
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19. Hypertension, blood pressure control and diabetic retinopathy in a large population-based study.

Author: Palazón-Bru, A, Liu, L, Quang, ND, Banu, R, Kumar, H, Tham, Y-C, Cheng, C-Y, Wong, TY, Sabanayagam, C, Palazón-Bru, A, Liu, L, Quang, ND, Banu, R, Kumar, H, Tham, Y-C, Cheng, C-Y, Wong, TY, and Sabanayagam, C
Abstract: BACKGROUND: Clinical trials have shown beneficial effects of blood pressure (BP) control in reducing the risk of diabetic retinopathy (DR). However, association between BP control and DR in population-based studies is not clear. We aimed to examine the association of hypertension and BP control with DR. METHODS: We analysed data from a population-based cross-sectional study of Chinese, Malay and Indians adults with diabetes and hypertension (2004-2011, n = 2189, aged 40-80 years) in Singapore. DR severity was assessed from retinal photographs and graded for any- and vision-threatening DR (VTDR) using the modified Airlie House classification. Hypertension status was classified into (1) good control: on treatment (SBP < 130 and DBP < 80 mm Hg), (2) moderate control: on treatment, with BP levels other than group 1 and 3, (3) poor control: on treatment (SBP ≥140 and DBP ≥ 90 mm Hg), (4) untreated hypertension, any BP level. SBP, DBP and pulse pressure (PP) were analyzed as categories and as continuous variables. The association between BP and DR was assessed using multivariable logistic regression models. RESULTS: The prevalence of any-DR and VTDR in the study population was 33.8% and 9.0% respectively. Both poorly controlled and untreated hypertension were significantly associated with any-DR with odds ratio (OR) (95% confidence interval [CI]) of 1.97 (1.39-2.83), and 2.01 [1.34-3.05]. Among BP components, SBP and PP were associated with both any-DR and VTDR with OR (95% CI) of 1.45 (1.28-1.65) and 1.61 (1.41-1.84) for any-DR, and 1.44 (1.19-1.76) and 1.67 (1.37-2.06) for VTDR. CONCLUSION: In a population-based sample of Asian adults with diabetes and hypertension, treated but poorly controlled as well as untreated hypertension were significantly associated with any-DR. Among the BP components, higher SBP and PP levels were associated with both any-DR and VTDR. Further longitudinal studies are necessary to confirm our findings.
Published: 2020

20. Rates and Determinants of Eyecare Utilization and Eyeglass Affordability Among Individuals With Visual Impairment in a Multi-Ethnic Population-Based Study in Singapore

Author: Gupta, P, Majithia, S, Fenwick, EK, Gan, ATL, Tham, Y-C, Poh, S, Thakur, S, Sabanayagam, C, Wong, TY, Cheng, C-Y, Lamoureux, EL, Gupta, P, Majithia, S, Fenwick, EK, Gan, ATL, Tham, Y-C, Poh, S, Thakur, S, Sabanayagam, C, Wong, TY, Cheng, C-Y, and Lamoureux, EL
Abstract: PURPOSE: The purpose of this study was to determine the rates of, and factors associated with, eyecare utilization and spectacle affordability among Singaporeans with vision impairment (VI). METHODS: We included adults with VI from their second visit of the Singapore Epidemiology of Eye Disease Study. Data on eyecare utilization and spectacle affordability were collected. Low eyecare utilization was defined as no eye check ever or eye checks not even once per year in reference to at least once per year. Difficulty affording glasses was defined as glasses being rated as expensive in reference to not expensive. RESULTS: There were 985 adults (14.5%; 415 Malays, 260 Indian, and 310 Chinese; mean age [SD]: 69.5 [10.2] years; 55.4% women) with VI who answered the above questions, were included. Of these, 624 (63.4%) wore glasses. The rates of low eyecare utilization and difficulty affording eyeglasses were 31% and 63%, respectively. Compared to Chinese (23.8%) and Indians (18.8%), Malays (57.4%) had the highest rates of low eyecare utilization (P < 0.001), and most difficulty affording eyeglasses (47.2% vs. 26.1% and 26.6% in Chinese and Indians, respectively; P < 0.001). Younger age, low socioeconomic status, absence of diabetes, absence of self-reported eye conditions, and poor vision were independently associated with low eyecare utilization, whereas older age and female sex was associated with difficulty affording glasses. CONCLUSIONS: In this multi-ethnic population with VI, almost one-third had low eyecare utilization and nearly two-thirds reported difficulty affording eyeglasses. TRANSLATIONAL RELEVANCE: This will inform strategies, such as tailored eyecare utilization awareness campaigns and awareness of available subsidy schemes for at-risk Singaporeans, such as Malays.
Published: 2020

21. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Author: Yonova-Doing, E, Zhao, W, Igo, RP, Wang, C, Sundaresan, P, Lee, KE, Jun, GR, Alves, AC, Chai, X, Chan, ASY, Lee, MC, Fong, A, Tan, AG, Khor, CC, Chew, EY, Hysi, PG, Fan, Q, Chua, J, Chung, J, Liao, J, Colijn, JM, Burdon, KP, Fritsche, LG, Swift, MK, Hilmy, MH, Chee, ML, Tedja, M, Bonnemaijer, PWM, Gupta, P, Tan, QS, Li, Z, Vithana, EN, Ravindran, RD, Chee, S-P, Shi, Y, Liu, W, Su, X, Sim, X, Shen, Y, Wang, YX, Li, H, Tham, Y-C, Teo, YY, Aung, T, Small, KS, Mitchell, P, Jonas, JB, Wong, TY, Fletcher, AE, Klaver, CCW, Klein, BEK, Wang, JJ, Iyengar, SK, Hammond, CJ, Cheng, C-Y, Yonova-Doing, E, Zhao, W, Igo, RP, Wang, C, Sundaresan, P, Lee, KE, Jun, GR, Alves, AC, Chai, X, Chan, ASY, Lee, MC, Fong, A, Tan, AG, Khor, CC, Chew, EY, Hysi, PG, Fan, Q, Chua, J, Chung, J, Liao, J, Colijn, JM, Burdon, KP, Fritsche, LG, Swift, MK, Hilmy, MH, Chee, ML, Tedja, M, Bonnemaijer, PWM, Gupta, P, Tan, QS, Li, Z, Vithana, EN, Ravindran, RD, Chee, S-P, Shi, Y, Liu, W, Su, X, Sim, X, Shen, Y, Wang, YX, Li, H, Tham, Y-C, Teo, YY, Aung, T, Small, KS, Mitchell, P, Jonas, JB, Wong, TY, Fletcher, AE, Klaver, CCW, Klein, BEK, Wang, JJ, Iyengar, SK, Hammond, CJ, and Cheng, C-Y
Abstract: Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10-16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10-19), TMPRSS5 (rs4936279, P = 2.5 × 10-10), LINC01412 (rs16823886, P = 1.3 × 10-9), GLTSCR1 (rs1005911, P = 9.8 × 10-9), and COMMD1 (rs62149908, P = 1.2 × 10-8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.
Published: 2020

22. Associations of autozygosity with a broad range of human phenotypes

Author: Clark, D.W. (David W), Okada, Y. (Yukinori), Moore, K.H.S. (Kristjan H S), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C.L.K. (Catriona L K), Lin, K. (Kuang), Zhao, J.H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, M.C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T.M. (Traci M), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M.J. (Matthew J), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D.L. (Diana), Dekker, A.M. (Annelot M), Eccles, D.A. (David A), Eijk, K.R. (Kristel) van, Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S.D. (Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. (John), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Sanghera, D.K. (Dharambir K), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M.B. (Matthias), Schunkert, H. (Heribert), Scott, R.A. (Robert), Shuldiner, A.R. (Alan R), Sim, X. (Xueling), Small, N. (Neil), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N.J. (Nicholas), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C.A. (Carol A), Weir, D.R. (David R), Whitfield, J. (John), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B.S. (Babette S.), Zonderman, A.B. (Alan B), Perola, M. (Markus), Magnusson, P.K. (Patrik), Uitterlinden, A.G. (André), Kooner, J.S. (Jaspal S.), Chasman, D.I. (Daniel), Loos, R.J.F. (Ruth), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. (Chris), Hayward, C. (Caroline), Walters, R.G. (Robin G), Perry, J.R.B. (John R. B.), Esko, T. (Tõnu), Helgason, A. (Agnar), Zwart, J-A. (John-Anker), Joshi, P.K. (Peter), Kubo, M. (Michiaki), Wilson, J.F. (James), Clark, D.W. (David W), Okada, Y. (Yukinori), Moore, K.H.S. (Kristjan H S), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C.L.K. (Catriona L K), Lin, K. (Kuang), Zhao, J.H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, M.C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T.M. (Traci M), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M.J. (Matthew J), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D.L. (Diana), Dekker, A.M. (Annelot M), Eccles, D.A. (David A), Eijk, K.R. (Kristel) van, Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S.D. (Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. (John), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Sanghera, D.K. (Dharambir K), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M.B. (Matthias), Schunkert, H. (Heribert), Scott, R.A. (Robert), Shuldiner, A.R. (Alan R), Sim, X. (Xueling), Small, N. (Neil), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N.J. (Nicholas), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C.A. (Carol A), Weir, D.R. (David R), Whitfield, J. (John), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B.S. (Babette S.), Zonderman, A.B. (Alan B), Perola, M. (Markus), Magnusson, P.K. (Patrik), Uitterlinden, A.G. (André), Kooner, J.S. (Jaspal S.), Chasman, D.I. (Daniel), Loos, R.J.F. (Ruth), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. (Chris), Hayward, C. (Caroline), Walters, R.G. (Robin G), Perry, J.R.B. (John R. B.), Esko, T. (Tõnu), Helgason, A. (Agnar), Zwart, J-A. (John-Anker), Joshi, P.K. (Peter), Kubo, M. (Michiaki), and Wilson, J.F. (James)
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Published: 2019
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23. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author: Teumer, A. (Alexander), Li, Y. (Yong), Ghasemi, S. (Sahar), Prins, B.P. (Bram Peter), Wuttke, M. (Matthias), Hermle, T. (Tobias), Giri, A. (Ayush), Sieber, K.B. (Karsten B.), Qiu, C. (Chengxiang), Kirsten, H. (Holger), Tin, A. (Adrienne), Chu, A.Y. (Audrey Y), Bansal, N. (Nisha), Feitosa, M.F. (Mary Furlan), Wang, L. (Lihua), Chai, J.-F. (Jin-Fang), Cocca, M. (Massimiliano), Fuchsberger, C. (Christian), Gorski, M. (Mathias), Hoppmann, A. (Anselm), Horn, K. (Katrin), Li, M. (Man), Marten, J. (Jonathan), Noce, D. (Damia), Nutile, T. (Teresa), Sedaghat, S. (Sanaz), Sveinbjornsson, G. (Gardar), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Xu, Y. (Yizhe), Yu, Z. (Zhi), Gerstner, L. (Lea), Ärnlöv, J. (Johan), Bakker, S.J.L. (Stephan), Baptista, D. (Daniela), Biggs, M.L. (M.), Boerwinkle, E.A. (Eric), Brenner, H. (Hermann), Burkhardt, R. (Ralph), Carroll, R.J. (Robert J.), Chee, M.-L. (Miao-Li), Chee, M.-L. (Miao-Ling), Chen, M. (Mengmeng), Cheng, C.-Y. (Ching-Yu), Cook, J.P. (James P.), Coresh, J. (Josef), Corre, T. (Tanguy), Danesh, J. (John), de Borst, M.H. (Martin H.), Grandi, A. (Alessandro) de, Mutsert, R. (Reneé) de, de Vries, A.P.J. (Aiko P J), Degenhardt, F. (Frauke), Dittrich, K. (Katalin), Divers, J. (Jasmin), Eckardt, K.-U. (Kai-Uwe), Ehret, G.B. (Georg), Endlich, K. (Karlhans), Felix, J.F. (Janine), Franco, O.H. (Oscar), Franke, A. (Andre), Freedman, B.I. (Barry), Freitag-Wolf, S. (Sandra), Gansevoort, R.T. (Ron), Giedraitis, V. (Vilmantas), Gögele, M. (Martin), Grundner-Culemann, F. (Franziska), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hamet, P. (Pavel), Harris, T.B. (Tamara), Hicks, A.A. (Andrew A.), Holm, H. (Hilma), Foo, V.H.X. (Valencia Hui Xian), Hwang, S.-J. (Shih-Jen), Ikram, M.A. (Arfan), Ingelsson, E. (Erik), Jaddoe, V.W.V. (Vincent), Jakobsdottir, M. (Margret), Josyula, N.S. (Navya Shilpa), Jung, B. (Bettina), Kähönen, M. (Mika), Khor, C.C., Kieß, W. (Wieland), Koenig, W. (Wolfgang), Körner, A. (Antje), Kovacs, P. (Peter), Kramer, H. (Holly), Krämer, B.K. (Bernhard), Kronenberg, F. (Florian), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Lee, J.J.-M. (Jeannette Jen-Mai), Lehtimäki, T. (Terho), Lieb, W. (Wolfgang), Lim, S.-C. (Su-Chi), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, J. (Jianjun), Loeffler, M. (Markus), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Maranville, J.C. (Joseph C.), Mascalzoni, D. (Deborah), McMullen, B. (Barbara), Meisinger, C. (Christa), Meitinger, T. (Thomas), Miliku, K. (Kozeta), Mook-Kanamori, D.O. (Dennis O.), Müller-Nurasyid, M. (Martina), Mychaleckyj, J.C. (Josyf), Nauck, M. (Matthias), Nikus, K. (Kjell), Ning, B. (Boting), Noordam, R. (Raymond), Connell, J.O. (Jeffrey O'), Olafsson, I. (Isleifur), Palmer, N.D. (Nicholette), Peters, A. (Annette), Podgornaia, A.I. (Anna I.), Ponte, B. (Belen), Poulain, T. (Tanja), Pramstaller, P.P. (Peter Paul), Rabelink, T. (Ton), Raffield, L.M. (Laura M.), Reilly, D.F. (Dermot F.), Rettig, R. (Rainer), Rheinberger, M. (Myriam), Rice, K.M. (Kenneth), Rivadeneira, F. (Fernando), Runz, H. (Heiko), Ryan, K.A. (Kathleen A.), Sabanayagam, C. (Charumathi), Saum, K.-U. (Kai-Uwe), Schöttker, B. (Ben), Shaffer, C.M. (Christian M.), Shi, Y. (Yuan), Smith, A.V. (Albert), Strauch, K. (Konstantin), Stumvoll, M. (Michael), Sun, B.B. (Benjamin B.), Szymczak, S. (Silke), Tai, E.-S. (E-Shyong), Tan, N.Y.Q. (Nicholas Y Q), Taylor, K.D. (Kent), Teren, A. (Andrej), Tham, Y.-C. (Yih-Chung), Thiery, J. (Joachim), Thio, C.H.L. (Chris H L), Thomsen, H. (Hauke), Thorsteinsdottir, U. (Unnur), Tönjes, A. (Anke), Tremblay, J. (Johanne), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Verweij, N. (Niek), Vogelezang, S., Völker, U. (Uwe), Waldenberger, M. (Melanie), Wang, C. (Chunliang), Wilson, O.D. (Otis D.), Wong, C. (Charlene), Wong, T.-Y. (Tien-Yin), Yang, Q. (Qiong), Yasuda, M. (Masayuki), Akilesh, S. (Shreeram), Bochud, M. (Murielle), Böger, C.A. (Carsten), Devuyst, O. (Olivier), Edwards, T.L. (Todd L.), Ho, K. (Kevin), Morris, A.P. (Andrew), Parsa, A. (Afshin), Pendergrass, S.A. (Sarah), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome I.), Zwart, J-A. (John-Anker), Wilson, J.F. (James), Susztak, K. (Katalin), Snieder, H. (Harold), Heid, I.M. (Iris), Scholz, M. (Markus), Butterworth, A.S. (Adam S.), Hung, A.M. (Adriana M.), Penninx, B.W.J.H., Köttgen, A. (Anna), Teumer, A. (Alexander), Li, Y. (Yong), Ghasemi, S. (Sahar), Prins, B.P. (Bram Peter), Wuttke, M. (Matthias), Hermle, T. (Tobias), Giri, A. (Ayush), Sieber, K.B. (Karsten B.), Qiu, C. (Chengxiang), Kirsten, H. (Holger), Tin, A. (Adrienne), Chu, A.Y. (Audrey Y), Bansal, N. (Nisha), Feitosa, M.F. (Mary Furlan), Wang, L. (Lihua), Chai, J.-F. (Jin-Fang), Cocca, M. (Massimiliano), Fuchsberger, C. (Christian), Gorski, M. (Mathias), Hoppmann, A. (Anselm), Horn, K. (Katrin), Li, M. (Man), Marten, J. (Jonathan), Noce, D. (Damia), Nutile, T. (Teresa), Sedaghat, S. (Sanaz), Sveinbjornsson, G. (Gardar), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Xu, Y. (Yizhe), Yu, Z. (Zhi), Gerstner, L. (Lea), Ärnlöv, J. (Johan), Bakker, S.J.L. (Stephan), Baptista, D. (Daniela), Biggs, M.L. (M.), Boerwinkle, E.A. (Eric), Brenner, H. (Hermann), Burkhardt, R. (Ralph), Carroll, R.J. (Robert J.), Chee, M.-L. (Miao-Li), Chee, M.-L. (Miao-Ling), Chen, M. (Mengmeng), Cheng, C.-Y. (Ching-Yu), Cook, J.P. (James P.), Coresh, J. (Josef), Corre, T. (Tanguy), Danesh, J. (John), de Borst, M.H. (Martin H.), Grandi, A. (Alessandro) de, Mutsert, R. (Reneé) de, de Vries, A.P.J. (Aiko P J), Degenhardt, F. (Frauke), Dittrich, K. (Katalin), Divers, J. (Jasmin), Eckardt, K.-U. (Kai-Uwe), Ehret, G.B. (Georg), Endlich, K. (Karlhans), Felix, J.F. (Janine), Franco, O.H. (Oscar), Franke, A. (Andre), Freedman, B.I. (Barry), Freitag-Wolf, S. (Sandra), Gansevoort, R.T. (Ron), Giedraitis, V. (Vilmantas), Gögele, M. (Martin), Grundner-Culemann, F. (Franziska), Gudbjartsson, D.F. (Daniel), Gudnason, V. (Vilmundur), Hamet, P. (Pavel), Harris, T.B. (Tamara), Hicks, A.A. (Andrew A.), Holm, H. (Hilma), Foo, V.H.X. (Valencia Hui Xian), Hwang, S.-J. (Shih-Jen), Ikram, M.A. (Arfan), Ingelsson, E. (Erik), Jaddoe, V.W.V. (Vincent), Jakobsdottir, M. (Margret), Josyula, N.S. (Navya Shilpa), Jung, B. (Bettina), Kähönen, M. (Mika), Khor, C.C., Kieß, W. (Wieland), Koenig, W. (Wolfgang), Körner, A. (Antje), Kovacs, P. (Peter), Kramer, H. (Holly), Krämer, B.K. (Bernhard), Kronenberg, F. (Florian), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Lee, J.J.-M. (Jeannette Jen-Mai), Lehtimäki, T. (Terho), Lieb, W. (Wolfgang), Lim, S.-C. (Su-Chi), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, J. (Jianjun), Loeffler, M. (Markus), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Maranville, J.C. (Joseph C.), Mascalzoni, D. (Deborah), McMullen, B. (Barbara), Meisinger, C. (Christa), Meitinger, T. (Thomas), Miliku, K. (Kozeta), Mook-Kanamori, D.O. (Dennis O.), Müller-Nurasyid, M. (Martina), Mychaleckyj, J.C. (Josyf), Nauck, M. (Matthias), Nikus, K. (Kjell), Ning, B. (Boting), Noordam, R. (Raymond), Connell, J.O. (Jeffrey O'), Olafsson, I. (Isleifur), Palmer, N.D. (Nicholette), Peters, A. (Annette), Podgornaia, A.I. (Anna I.), Ponte, B. (Belen), Poulain, T. (Tanja), Pramstaller, P.P. (Peter Paul), Rabelink, T. (Ton), Raffield, L.M. (Laura M.), Reilly, D.F. (Dermot F.), Rettig, R. (Rainer), Rheinberger, M. (Myriam), Rice, K.M. (Kenneth), Rivadeneira, F. (Fernando), Runz, H. (Heiko), Ryan, K.A. (Kathleen A.), Sabanayagam, C. (Charumathi), Saum, K.-U. (Kai-Uwe), Schöttker, B. (Ben), Shaffer, C.M. (Christian M.), Shi, Y. (Yuan), Smith, A.V. (Albert), Strauch, K. (Konstantin), Stumvoll, M. (Michael), Sun, B.B. (Benjamin B.), Szymczak, S. (Silke), Tai, E.-S. (E-Shyong), Tan, N.Y.Q. (Nicholas Y Q), Taylor, K.D. (Kent), Teren, A. (Andrej), Tham, Y.-C. (Yih-Chung), Thiery, J. (Joachim), Thio, C.H.L. (Chris H L), Thomsen, H. (Hauke), Thorsteinsdottir, U. (Unnur), Tönjes, A. (Anke), Tremblay, J. (Johanne), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Verweij, N. (Niek), Vogelezang, S., Völker, U. (Uwe), Waldenberger, M. (Melanie), Wang, C. (Chunliang), Wilson, O.D. (Otis D.), Wong, C. (Charlene), Wong, T.-Y. (Tien-Yin), Yang, Q. (Qiong), Yasuda, M. (Masayuki), Akilesh, S. (Shreeram), Bochud, M. (Murielle), Böger, C.A. (Carsten), Devuyst, O. (Olivier), Edwards, T.L. (Todd L.), Ho, K. (Kevin), Morris, A.P. (Andrew), Parsa, A. (Afshin), Pendergrass, S.A. (Sarah), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome I.), Zwart, J-A. (John-Anker), Wilson, J.F. (James), Susztak, K. (Katalin), Snieder, H. (Harold), Heid, I.M. (Iris), Scholz, M. (Markus), Butterworth, A.S. (Adam S.), Hung, A.M. (Adriana M.), Penninx, B.W.J.H., and Köttgen, A. (Anna)
Abstract: Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
Published: 2019
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24. Associations of autozygosity with a broad range of human phenotypes

Author: Clark, D. W. (David W.), Okada, Y. (Yukinori), Moore, K. H. (Kristjan H. S.), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C. L. (Catriona L. K.), Lin, K. (Kuang), Zhao, J. H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T. M. (Traci M.), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M. J. (Matthew J.), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D. L. (Diana L.), Dekker, A. M. (Annelot M.), Eccles, D. A. (David A.), Van Eijk, K. R. (Kristel R.), Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S. D. (Scott D.), de Haan, H. G. (Hugoline G.), Harris, S. E. (Sarah E.), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. E. (Iris E.), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M. E. (Marcus E.), Li, S. A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M. E. (May E.), van der Most, P. J. (Peter J.), Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R. B. (Rashmi B.), Priyanka, T. D. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B. R. (Bishwa R.), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M. C. (Melissa C.), Smith, A. V. (Albert Vernon), van der Spek, A. (Ashley), Spracklen, C. N. (Cassandra N.), Strawbridge, R. J. (Rona J.), Tajuddin, S. M. (Salman M.), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. R. (Helen R.), Wootton, R. E. (Robyn E.), Yanek, L. R. (Lisa R.), Yao, J. (Jie), Yousri, N. A. (Noha A.), Zhao, W. (Wei), Adeyemo, A. A. (Adebowale A.), Afaq, S. (Saima), Alberto Aguilar-Salinas, C. (Carlos), Akiyama, M. (Masato), Albert, M. L. (Matthew L.), Allison, M. A. (Matthew A.), Alver, M. (Maris), Aung, T. (Tin), Azizi, F. (Fereidoun), Bentley, A. R. (Amy R.), Boeing, H. (Heiner), Boerwinkle, E. (Eric), Borja, J. B. (Judith B.), de Borst, G. J. (Gert J.), Bottinger, E. P. (Erwin P.), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y. I. (Yii-Der I.), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F. S. (Francis S.), Concas, M. P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Van Dam, R. M. (Rob M.), Damulina, A. (Anna), Daneshpour, M. S. (Maryam S.), Day, F. R. (Felix R.), Delgado, G. E. (Graciela E.), Dhana, K. (Klodian), Doney, A. S. (Alexander S. F.), Doerr, M. (Marcus), Doumatey, A. P. (Ayo P.), Dzimiri, N. (Nduna), Ebenesersdottir, S. S. (S. Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J. F. (Janine F.), Fischer, K. (Krista), Freedman, B. I. (Barry I.), Girotto, G. (Giorgia), Goel, A. (Anuj), Gogele, M. (Martin), Goodarzi, M. O. (Mark O.), Graff, M. (Mariaelisa), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D. F. (Daniel F.), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S. P. (Saskia P.), Haiman, C. A. (Christopher A.), Halevy, A. (Avner), Harris, T. B. (Tamara B.), Hedayati, M. (Mehdi), van Heel, D. A. (David A.), Hirata, M. (Makoto), Hofer, I. (Imo), Hsiung, C. A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M. A. (M. Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N. D. (Nicola D.), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C. C. (Chiea Chuen), de Kleijn, D. P. (Dominique P. V.), Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Kramer, B. K. (Bernhard K.), Kutalik, Z. (Zoltan), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L. J. (Lenore J.), Lawlor, D. A. (Deborah A.), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. M. (Markus M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S. J. (Stephanie J.), Loomis, S. (Stephanie), Lu, Y. (Yingchang), Luan, J. (Jian'an), Magi, R. (Reedik), Manichaikul, A. W. (Ani W.), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X. W. (Xue W.), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I. Y. (Iona Y.), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (Pierre-Emmanuel), Moreno-Macias, H. (Hortensia), Mori, T. A. (Trevor A.), Morrison, A. C. (Alanna C.), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A. D. (Alison D.), de Mutsert, R. (Renee), Mychaleckyj, J. C. (Josyf C.), Nalls, M. A. (Mike A.), Nauck, M. (Matthias), Neville, M. J. (Matt J.), Nolte, I. M. (Ilja M.), Ong, K. K. (Ken K.), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Palsson, G. (Gunnar), Pankow, J. S. (James S.), Pattaro, C. (Cristian), Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N. (Neil), Pramstaller, P. P. (Peter P.), Quintana-Murci, L. (Lluis), Raikkonen, K. (Katri), Ralhan, S. (Sarju), Rao, D. C. (Dabeeru C.), van Rheenen, W. (Wouter), Rich, S. S. (Stephen S.), Ridker, P. M. (Paul M.), Rietveld, C. A. (Cornelius A.), Robino, A. (Antonietta), van Rooij, F. J. (Frank J. A.), Ruggiero, D. (Daniela), Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Felicita Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L. J. (Laura J.), Scott, W. R. (William R.), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), van Setten, J. (Jessica), Sever, P. J. (Peter J.), Sheu, W. H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S. R. (Sharvari Rahul), Sigurdsson, J. K. (Jon K.), Sikka, T. T. (Timo Tonis), Singh, J. R. (Jai Rup), Smith, B. H. (Blair H.), Stancakova, A. (Alena), Stanton, A. (Alice), Starr, J. M. (John M.), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M. A. (Morris A.), Taylor, A. M. (Adele M.), Taylor, K. D. (Kent D.), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R. P. (Russell P.), Tusie-Luna, T. (Teresa), Tzoulaki, I. (Ioanna), Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J. H. (Jan H.), Vitart, V. (Veronique), Volker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S. M. (Salma M.), Waldenberger, M. (Melanie), Wander, G. S. (Gurpreet S.), Wang, Y. X. (Ya Xing), Wareham, N. J. (Nicholas J.), Wild, S. (Sarah), Yajnik, C. S. (Chittaranjan S.), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F. W. (Folkert W.), Bakker, S. J. (Stephan J. L.), Becker, D. M. (Diane M.), Lehne, B. (Benjamin), Bennett, D. A. (David A.), van den Berg, L. H. (Leonard H.), Berndt, S. I. (Sonja I.), Bharadwaj, D. (Dwaipayan), Bielak, L. F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Mike), Bouchard, C. (Claude), Bradfield, J. P. (Jonathan P.), Brody, J. A. (Jennifer A.), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. J. (Mark J.), Cesarini, D. (David), Chambers, J. C. (John C.), Chandak, G. R. (Giriraj Ratan), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Cornelis, M. (Marilyn), Cusi, D. (Daniele), Smith, G. D. (George Davey), Deary, I. J. (Ian J.), Dorajoo, R. (Rajkumar), van Duijn, C. M. (Cornelia M.), Ellinghaus, D. (David), Erdmann, J. (Jeanette), Eriksson, J. G. (Johan G.), Evangelou, E. (Evangelos), Evans, M. K. (Michele K.), Faul, J. D. (Jessica D.), Feenstra, B. (Bjarke), Feitosa, M. (Mary), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S. F. (Struan F. A.), Griffiths, L. R. (Lyn R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), van der Harst, P. (Pim), Heng, C.-K. (Chew-Kiat), Hicks, A. A. (Andrew A.), Hochner, H. (Hagit), Huikuri, H. (Heikki), Hunt, S. C. (Steven C.), Jaddoe, V. W. (Vincent W. V.), De Jager, P. L. (Philip L.), Johannesson, M. (Magnus), Johansson, A. (Asa), Jonas, J. B. (Jost B.), Jukema, J. W. (J. Wouter), Junttila, J. (Juhani), Kaprio, J. (Jaakko), Kardia, S. L. (Sharon L. R.), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S. W. (Sander W.), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R. A. (Rodney A.), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N. G. (Nicholas G.), Marz, W. (Winfried), Matullo, G. (Giuseppe), McCarthy, M. I. (Mark I.), Medland, S. E. (Sarah E.), Merriman, T. R. (Tony R.), Metspalu, A. (Andres), Meyer, B. F. (Brian F.), Mohlke, K. L. (Karen L.), Montgomery, G. W. (Grant W.), Mook-Kanamori, D. (Dennis), Munroe, P. B. (Patricia B.), North, K. E. (Kari E.), Nyholt, D. R. (Dale R.), O'connell, J. R. (Jeffery R.), Ober, C. (Carole), Oldehinkel, A. J. (Albertine J.), Palmas, W. (Walter), Palmer, C. (Colin), Pasterkamp, G. G. (Gerard G.), Patin, E. (Etienne), Pennell, C. E. (Craig E.), Perusse, L. (Louis), Peyser, P. A. (Patricia A.), Pirastu, M. (Mario), Polderman, T. J. (Tinca J. C.), Porteous, D. J. (David J.), Posthuma, D. (Danielle), Psaty, B. M. (Bruce M.), Rioux, J. D. (John D.), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J. I. (Jerome I.), Rudan, I. (Igor), Den Ruijter, H. M. (Hester M.), Sanghera, D. K. (Dharambir K.), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M. B. (Matthias B.), Schunkert, H. (Heribert), Scott, R. A. (Robert A.), Shuldiner, A. R. (Alan R.), Sim, X. (Xueling), Small, N. (Neil), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N. J. (Nicholas J.), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C. A. (Carol A.), Weir, D. R. (David R.), Whitfield, J. B. (John B.), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B. S. (Babette S.), Zonderman, A. B. (Alan B.), Perola, M. (Markus), Magnusson, P. K. (Patrik K. E.), Uitterlinden, A. G. (Andre G.), Kooner, J. S. (Jaspal S.), Chasman, D. I. (Daniel I.), Loos, R. J. (Ruth J. F.), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. S. (Chris S.), Hayward, C. (Caroline), Walters, R. G. (Robin G.), Perry, J. R. (John R. B.), Esko, T. (Tonu), Helgason, A. (Agnar), Stefansson, K. (Kari), Joshi, P. K. (Peter K.), Kubo, M. (Michiaki), Wilson, J. F. (James F.), Clark, D. W. (David W.), Okada, Y. (Yukinori), Moore, K. H. (Kristjan H. S.), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C. L. (Catriona L. K.), Lin, K. (Kuang), Zhao, J. H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T. M. (Traci M.), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M. J. (Matthew J.), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D. L. (Diana L.), Dekker, A. M. (Annelot M.), Eccles, D. A. (David A.), Van Eijk, K. R. (Kristel R.), Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S. D. (Scott D.), de Haan, H. G. (Hugoline G.), Harris, S. E. (Sarah E.), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. E. (Iris E.), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M. E. (Marcus E.), Li, S. A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M. E. (May E.), van der Most, P. J. (Peter J.), Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R. B. (Rashmi B.), Priyanka, T. D. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B. R. (Bishwa R.), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M. C. (Melissa C.), Smith, A. V. (Albert Vernon), van der Spek, A. (Ashley), Spracklen, C. N. (Cassandra N.), Strawbridge, R. J. (Rona J.), Tajuddin, S. M. (Salman M.), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. R. (Helen R.), Wootton, R. E. (Robyn E.), Yanek, L. R. (Lisa R.), Yao, J. (Jie), Yousri, N. A. (Noha A.), Zhao, W. (Wei), Adeyemo, A. A. (Adebowale A.), Afaq, S. (Saima), Alberto Aguilar-Salinas, C. (Carlos), Akiyama, M. (Masato), Albert, M. L. (Matthew L.), Allison, M. A. (Matthew A.), Alver, M. (Maris), Aung, T. (Tin), Azizi, F. (Fereidoun), Bentley, A. R. (Amy R.), Boeing, H. (Heiner), Boerwinkle, E. (Eric), Borja, J. B. (Judith B.), de Borst, G. J. (Gert J.), Bottinger, E. P. (Erwin P.), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y. I. (Yii-Der I.), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F. S. (Francis S.), Concas, M. P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Van Dam, R. M. (Rob M.), Damulina, A. (Anna), Daneshpour, M. S. (Maryam S.), Day, F. R. (Felix R.), Delgado, G. E. (Graciela E.), Dhana, K. (Klodian), Doney, A. S. (Alexander S. F.), Doerr, M. (Marcus), Doumatey, A. P. (Ayo P.), Dzimiri, N. (Nduna), Ebenesersdottir, S. S. (S. Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J. F. (Janine F.), Fischer, K. (Krista), Freedman, B. I. (Barry I.), Girotto, G. (Giorgia), Goel, A. (Anuj), Gogele, M. (Martin), Goodarzi, M. O. (Mark O.), Graff, M. (Mariaelisa), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D. F. (Daniel F.), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S. P. (Saskia P.), Haiman, C. A. (Christopher A.), Halevy, A. (Avner), Harris, T. B. (Tamara B.), Hedayati, M. (Mehdi), van Heel, D. A. (David A.), Hirata, M. (Makoto), Hofer, I. (Imo), Hsiung, C. A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M. A. (M. Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N. D. (Nicola D.), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C. C. (Chiea Chuen), de Kleijn, D. P. (Dominique P. V.), Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Kramer, B. K. (Bernhard K.), Kutalik, Z. (Zoltan), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L. J. (Lenore J.), Lawlor, D. A. (Deborah A.), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. M. (Markus M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S. J. (Stephanie J.), Loomis, S. (Stephanie), Lu, Y. (Yingchang), Luan, J. (Jian'an), Magi, R. (Reedik), Manichaikul, A. W. (Ani W.), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X. W. (Xue W.), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I. Y. (Iona Y.), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (Pierre-Emmanuel), Moreno-Macias, H. (Hortensia), Mori, T. A. (Trevor A.), Morrison, A. C. (Alanna C.), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A. D. (Alison D.), de Mutsert, R. (Renee), Mychaleckyj, J. C. (Josyf C.), Nalls, M. A. (Mike A.), Nauck, M. (Matthias), Neville, M. J. (Matt J.), Nolte, I. M. (Ilja M.), Ong, K. K. (Ken K.), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Palsson, G. (Gunnar), Pankow, J. S. (James S.), Pattaro, C. (Cristian), Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N. (Neil), Pramstaller, P. P. (Peter P.), Quintana-Murci, L. (Lluis), Raikkonen, K. (Katri), Ralhan, S. (Sarju), Rao, D. C. (Dabeeru C.), van Rheenen, W. (Wouter), Rich, S. S. (Stephen S.), Ridker, P. M. (Paul M.), Rietveld, C. A. (Cornelius A.), Robino, A. (Antonietta), van Rooij, F. J. (Frank J. A.), Ruggiero, D. (Daniela), Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Felicita Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L. J. (Laura J.), Scott, W. R. (William R.), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), van Setten, J. (Jessica), Sever, P. J. (Peter J.), Sheu, W. H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S. R. (Sharvari Rahul), Sigurdsson, J. K. (Jon K.), Sikka, T. T. (Timo Tonis), Singh, J. R. (Jai Rup), Smith, B. H. (Blair H.), Stancakova, A. (Alena), Stanton, A. (Alice), Starr, J. M. (John M.), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M. A. (Morris A.), Taylor, A. M. (Adele M.), Taylor, K. D. (Kent D.), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R. P. (Russell P.), Tusie-Luna, T. (Teresa), Tzoulaki, I. (Ioanna), Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J. H. (Jan H.), Vitart, V. (Veronique), Volker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S. M. (Salma M.), Waldenberger, M. (Melanie), Wander, G. S. (Gurpreet S.), Wang, Y. X. (Ya Xing), Wareham, N. J. (Nicholas J.), Wild, S. (Sarah), Yajnik, C. S. (Chittaranjan S.), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F. W. (Folkert W.), Bakker, S. J. (Stephan J. L.), Becker, D. M. (Diane M.), Lehne, B. (Benjamin), Bennett, D. A. (David A.), van den Berg, L. H. (Leonard H.), Berndt, S. I. (Sonja I.), Bharadwaj, D. (Dwaipayan), Bielak, L. F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Mike), Bouchard, C. (Claude), Bradfield, J. P. (Jonathan P.), Brody, J. A. (Jennifer A.), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. J. (Mark J.), Cesarini, D. (David), Chambers, J. C. (John C.), Chandak, G. R. (Giriraj Ratan), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Cornelis, M. (Marilyn), Cusi, D. (Daniele), Smith, G. D. (George Davey), Deary, I. J. (Ian J.), Dorajoo, R. (Rajkumar), van Duijn, C. M. (Cornelia M.), Ellinghaus, D. (David), Erdmann, J. (Jeanette), Eriksson, J. G. (Johan G.), Evangelou, E. (Evangelos), Evans, M. K. (Michele K.), Faul, J. D. (Jessica D.), Feenstra, B. (Bjarke), Feitosa, M. (Mary), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S. F. (Struan F. A.), Griffiths, L. R. (Lyn R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), van der Harst, P. (Pim), Heng, C.-K. (Chew-Kiat), Hicks, A. A. (Andrew A.), Hochner, H. (Hagit), Huikuri, H. (Heikki), Hunt, S. C. (Steven C.), Jaddoe, V. W. (Vincent W. V.), De Jager, P. L. (Philip L.), Johannesson, M. (Magnus), Johansson, A. (Asa), Jonas, J. B. (Jost B.), Jukema, J. W. (J. Wouter), Junttila, J. (Juhani), Kaprio, J. (Jaakko), Kardia, S. L. (Sharon L. R.), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S. W. (Sander W.), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R. A. (Rodney A.), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N. G. (Nicholas G.), Marz, W. (Winfried), Matullo, G. (Giuseppe), McCarthy, M. I. (Mark I.), Medland, S. E. (Sarah E.), Merriman, T. R. (Tony R.), Metspalu, A. (Andres), Meyer, B. F. (Brian F.), Mohlke, K. L. (Karen L.), Montgomery, G. W. (Grant W.), Mook-Kanamori, D. (Dennis), Munroe, P. B. (Patricia B.), North, K. E. (Kari E.), Nyholt, D. R. (Dale R.), O'connell, J. R. (Jeffery R.), Ober, C. (Carole), Oldehinkel, A. J. (Albertine J.), Palmas, W. (Walter), Palmer, C. (Colin), Pasterkamp, G. G. (Gerard G.), Patin, E. (Etienne), Pennell, C. E. (Craig E.), Perusse, L. (Louis), Peyser, P. A. (Patricia A.), Pirastu, M. (Mario), Polderman, T. J. (Tinca J. C.), Porteous, D. J. (David J.), Posthuma, D. (Danielle), Psaty, B. M. (Bruce M.), Rioux, J. D. (John D.), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J. I. (Jerome I.), Rudan, I. (Igor), Den Ruijter, H. M. (Hester M.), Sanghera, D. K. (Dharambir K.), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M. B. (Matthias B.), Schunkert, H. (Heribert), Scott, R. A. (Robert A.), Shuldiner, A. R. (Alan R.), Sim, X. (Xueling), Small, N. (Neil), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N. J. (Nicholas J.), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C. A. (Carol A.), Weir, D. R. (David R.), Whitfield, J. B. (John B.), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B. S. (Babette S.), Zonderman, A. B. (Alan B.), Perola, M. (Markus), Magnusson, P. K. (Patrik K. E.), Uitterlinden, A. G. (Andre G.), Kooner, J. S. (Jaspal S.), Chasman, D. I. (Daniel I.), Loos, R. J. (Ruth J. F.), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. S. (Chris S.), Hayward, C. (Caroline), Walters, R. G. (Robin G.), Perry, J. R. (John R. B.), Esko, T. (Tonu), Helgason, A. (Agnar), Stefansson, K. (Kari), Joshi, P. K. (Peter K.), Kubo, M. (Michiaki), and Wilson, J. F. (James F.)
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Published: 2019

25. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author: TEDJA, M. S., WOJCIECHOWSKI, R., HYSI, P. G., ERIKSSON, N., FURLOTTE, N. A., VERHOEVEN, V. J. M., IGLESIAS, A. I., MEESTER-SMOOR, M. A., TOMPSON, S. W., Fan, Q., KHAWAJA, A. P., CHENG, C. Y., HOHN, R., YAMASHIRO, K., WENOCUR, A., GRAZAL, C., Haller, T., Metspalu, A., WEDENOJA, J., JONAS, J. B., WANG, Y. X., Xie, J., Mitchell, P., FOSTER, P. J., KLEIN, B. E. K., Klein, R., PATERSON, A. D., HOSSEINI, S. M., SHAH, R. L., Williams, C., TEO, Y. Y., THAM, Y. C., Gupta, P., Zhao, W., Shi, Y., SAW, W. Y., TAI, E. S., SIM, X. L., HUFFMAN, J. E., POLASEK, O., Hayward, C., BENCIC, G., RUDAN, I., WILSON, J. F., Joshi, P. K., TSUJIKAWA, A., Matsuda, F., WHISENHUNT, K. N., Zeller, T., VAN DER SPEK, P. J., HAAK, R., Meijers-Heijboer, H., VAN LEEUWEN, E. M., IYENGAR, S. K., LASS, J. H., Hofman, A., Rivadeneira, F., UITTERLINDEN, A. G., VINGERLING, J. R., LEHTIMAKI, T., RAITAKARI, O. T., BIINO, G., CONCAS, M. P., SCHWANTES-AN, T. H., IGO, R. P., Jr., CUELLAR-PARTIDA, G., Martin, N. G., CRAIG, J. E., GHARAHKHANI, P., Williams, K. M., NAG, A., RAHI, J. S., CUMBERLAND, P. M., Delcourt, Cécile, Bellenguez, C., RIED, J. S., BERGEN, A. A., Meitinger, T., Gieger, C., WONG, T. Y., HEWITT, A. W., MACKEY, D. A., SIMPSON, C. L., Pfeiffer, N., PARSSINEN, O., BAIRD, P. N., Vitart, V., Amin, N., VAN DUIJN, C. M., BAILEY-WILSON, J. E., YOUNG, T. L., SAW, S. M., STAMBOLIAN, D., MACGREGOR, S., GUGGENHEIM, J. A., TUNG, J. Y., HAMMOND, C. J., KLAVER, C. C. W., Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, LEHA
Abstract: Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
Published: 2018
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26. Risk of Incident Cardiovascular Disease and Cardiovascular Risk Factors in First and Second-Generation Indians: The Singapore Indian Eye Study

Author: Gupta, P, Gan, ATL, Man, REK, Fenwick, EK, Tham, Y-C, Sabanayagam, C, Wong, TY, Cheng, C-Y, Lamoureux, EL, Gupta, P, Gan, ATL, Man, REK, Fenwick, EK, Tham, Y-C, Sabanayagam, C, Wong, TY, Cheng, C-Y, and Lamoureux, EL
Abstract: Population-based data investigating generational differences in the risk of incident cardiovascular disease (CVD) and its risk determinants are rare. We examined the 6-year incidence of CVD and its risk factors in first- and second-generation ethnic Indians living in Singapore. 1749 participants (mean age [SD]: 55.5 [8.8] years; 47.5% male) from a population-based, longitudinal study of Indian adults were included for incident CVD outcome. Incident CVD was defined as self-reported myocardial infarction, angina pectoris or stroke which developed between baseline and follow-up. CVD-related risk factors included incident diabetes, hypertension, hyperlipidemia, obesity and chronic kidney disease (CKD). For incident CVD outcome, of the 1749 participants, 406 (23.2%) and 1343 (76.8%) were first and second-generation Indians, respectively. Of these, 73 (4.1%) reported incident CVD. In multivariable models, second-generation individuals had increased risk of developing CVD (RR = 2.04; 95% CI 1.04, 3.99; p = 0.038), hyperlipidemia (RR = 1.27; 95% CI 1.06, 1.53; p = 0.011), and CKD (RR = 1.92; 95% CI 1.22, 3.04; p = 0.005), compared to first-generation Indians. Second-generation Indians have increased risk of developing CVD and its associated risk factors such as hyperlipidemia and CKD compared to first-generation immigrants, independent of traditional CVD risk factors. More stratified and tailored CVD prevention strategies on second and subsequent generations of Indian immigrants in Singapore are warranted.
Published: 2018

27. Diagnostic accuracy of macular ganglion cell-inner plexiform layer thickness for glaucoma detection in a population-based study: Comparison with optic nerve head imaging parameters.

Author: Belghith, A, Koh, V, Tham, Y-C, Cheung, CY, Mani, B, Wong, TY, Aung, T, Cheng, C-Y, Belghith, A, Koh, V, Tham, Y-C, Cheung, CY, Mani, B, Wong, TY, Aung, T, and Cheng, C-Y
Abstract: AIMS: To determine the diagnostic performance of macular ganglion cell-inner plexiform layer (GCIPL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) for glaucoma detection in a Chinese population in comparison with optic nerve head (ONH) and retinal nerve fiber layer (RNFL) parameters measured by both SD-OCT and Heidelberg Retina Tomography 3 (HRT-3). METHODS: Adults aged 40 to 80 years were recruited from the population-based study (n = 3353, response rate 72.8%). Macular cube 200x200 scan was performed with Cirrus SD-OCT (version 6.0, Carl Zeiss Meditec Inc, Dublin, CA) for GCIPL thickness measurement. ONH and RNFL imaging was performed with Cirrus SD-OCT and HRT-3 (Heidelberg Engineering, Heidelberg, Germany). Glaucoma was defined according to International Society for Geographical and Epidemiological Ophthalmology criteria. RESULTS: In total, 86 eyes of 60 subjects with glaucoma and 1709 eyes of 1001 non-glaucoma participants were included. The best performing parameters for Cirrus SD-OCT GCIPL, Cirrus SD-OCT ONH and HRT-3 were minimum GCIPL thickness (Area under receiver-operating curve [AUC] = 0.89, 95% CI 0.83-0.95), vertical cup-disc ratio (CDR) (AUC = 0.94, 0.91-0.98) and vertical CDR (AUC = 0.86, 0.81-0.92), respectively. At 85% specificity, vertical CDR measured using Cirrus OCT ONH scan showed the highest sensitivity (88.64%, 95% CI 75.4-96.2) compared to minimum GCIPL thickness with sensitivity of 60.53% (95% CI 46.4-73.0) (p<0.001). Inferior RNFL thickness (AUC = 0.84, 95% CI 0.91-0.97) measured by Cirrus SD-OCT was also superior to Cirrus SD-OCT GCIPL (p<0.007). CONCLUSIONS: The diagnostic performance of macular GCIPL scan is inferior compared to vertical CDR measured by Cirrus OCT ONH scan. Cirrus OCT ONH scan showed the best ability in detecting glaucoma in a Chinese population, suggesting it could be a good glaucoma screening tool in an Asian population.
Published: 2018

28. Falls and Recurrent Falls among Adults in A Multi-ethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study

Author: Dai, W, Tham, Y-C, Chee, M-L, Tan, NYQ, Wong, K-H, Majithia, S, Sabanayagam, C, Lamoureux, E, Wong, T-Y, Cheng, C-Y, Dai, W, Tham, Y-C, Chee, M-L, Tan, NYQ, Wong, K-H, Majithia, S, Sabanayagam, C, Lamoureux, E, Wong, T-Y, and Cheng, C-Y
Abstract: We evaluated the rate and risk factors associated with falls and recurrent falls in a multi-ethnic Asian population. 10,009 participants aged ≥40 years (mean[SD] age = 58.9[10.4] years) underwent clinical examinations and completed interviewer-administered questionnaires. Participants who self-reported at least one fall or ≥2 falls in past 12 months were defined as fallers and recurrent fallers, respectively. Age-standardized rates for falls and recurrent falls were 13.8% (95%CI, 13.1-14.6%) and 4.6% (95%CI, 4.2-5.1%), respectively. Multivariable analyses showed older age (OR = 1.20; 95%CI, 1.11-1.30), female gender (OR = 1.79; 95%CI, 1.54-2.07), diabetes (OR = 1.22; 95%CI, 1.07-1.40), cardiovascular disease (CVD, OR = 1.37; 95%CI, 1.14-1.65), ≥3 systemic comorbidities (OR = 1.35; 95%CI, 1.09-1.67), lower European Quality of Life-5 Dimensions (EQ-5D) score (OR = 1.36; 95%CI, 1.29-1.44), alcohol consumption (OR = 1.41, 95%CI, 1.11-1.78) and presenting visual impairment (VI, OR = 1.23; 95%CI, 1.02-1.47) were associated with falls. For recurrent falls, female gender (OR = 2.27; 95%CI, 1.75-2.94), diabetes (OR = 1.28; 95%CI, 1.03-1.61), CVD (OR = 2.00; 95%CI, 1.53-2.62), ≥3 systemic comorbidities (OR = 1.69; 95%CI, 1.19-2.39), lower EQ-5D score (OR = 1.47; 95%CI, 1.35-1.59), living in 1-2 room public flat (OR = 1.57; 95%CI, 1.05-2.33), monthly income <2000 Singapore Dollar (OR = 1.62; 95%CI, 1.13-2.31), alcohol consumption (OR = 1.81, 95%CI, 1.23-2.66) and presenting VI (OR = 1.34; 95%CI, 1.01-1.79) were significant risk factors. These findings will be useful for the formulation of fall prevention programs.
Published: 2018

29. Trends of Visual Impairment and Blindness in the Singapore Chinese Population over a Decade.

Author: Tham, Y-C, Lim, S-H, Shi, Y, Chee, M-L, Zheng, YF, Chua, J, Saw, S-M, Foster, P, Aung, T, Wong, TY, Cheng, C-Y, Tham, Y-C, Lim, S-H, Shi, Y, Chee, M-L, Zheng, YF, Chua, J, Saw, S-M, Foster, P, Aung, T, Wong, TY, and Cheng, C-Y
Abstract: We evaluated the prevalence of visual impairment (VI) and blindness among Chinese adults in the Singapore Chinese Eye Study (SCES, 2009-2011), and compared the trends with the Tanjong Pagar Survey, Singapore (TPS), conducted a decade earlier. The SCES comprised of 3,353 Chinese adults aged ≥40 years (response rate, 72.8%). Participants underwent standardized examinations, including measurements of presenting, and best-corrected visual acuity (VA). Bilateral VI (VA < 20/40 to ≥20/200) and blindness (VA < 20/200) were defined based on the United States definition (better-seeing eye). Age-standardized prevalence was calculated using the 2010 Singapore Chinese Population Census. Primary causes and factors associated with VI and blindness were evaluated. In SCES, the age-standardized prevalence of presenting bilateral VI and blindness were 17.7% and 0.6%, respectively; the age-standardised prevalence of best-corrected bilateral VI and blindness were 3.4% and 0.2%, respectively. The previous TPS reported similar rates of best-corrected bilateral VI (3.8%) and blindness (0.3%). In SCES, cataract remains the main cause for both best-corrected bilateral VI (76.0%) and blindness (50.0%). Older age, female, lower income, lower educational level, and smaller housing type were associated with presenting bilateral VI or blindness (all P ≤ 0.025). These findings will be useful for the planning of eye care services and resource allocation.
Published: 2018

30. Associations between sleep duration, sleep quality and diabetic retinopathy

Author: Pan, C-W, Tan, NYQ, Chew, M, Tham, Y-C, Quang, DN, Yasuda, M, Cheng, C-Y, Wong, TY, Sabanayagam, C, Pan, C-W, Tan, NYQ, Chew, M, Tham, Y-C, Quang, DN, Yasuda, M, Cheng, C-Y, Wong, TY, and Sabanayagam, C
Abstract: BACKGROUND: Abnormal durations of sleep have been associated with risk of diabetes. However, it is not clear if sleep duration is associated with diabetic retinopathy (DR). METHODS: In a cross-sectional study, we included 1,231 (Malay, n = 395; Indian, n = 836) adults (mean age 64.4 ± 9.0 years, 50.4% female) with diabetes from the second visit of two independent population-based cohort studies (2011-15) in Singapore. Self-reported habitual sleep duration was categorized as short (<6 h), normal (6≤ h <8), and long (≥8 h). Questionnaires were administered to detect risk of obstructive sleep apnea (OSA), excessive daytime sleepiness, and insomnia, all of which may indicate poor quality of sleep. The associations between sleep-related characteristics with moderate DR and vision-threatening DR (VTDR) were analysed using logistic regression models adjusted for potential confounders. RESULTS: Prevalence of moderate DR and VTDR in the study population were 10.5% and 6.3% respectively. The mean duration of sleep was 6.4 ± 1.5 h. Compared to normal sleep duration, both short and long sleep durations were associated with moderate DR with multivariable odds ratio (95% confidence interval) of 1.73 (1.03-2.89) and 2.17 (1.28-3.66) respectively. Long sleep duration (2.37 [1.16-4.89]), high risk of OSA (2.24 [1.09-4.75]), and excessive daytime sleepiness (3.27 [1.02-10.30]) were separately associated with VTDR. CONCLUSION: Sleep duration had a U-shaped association with moderate DR; long sleep duration, excessive daytime sleepiness and high risk of OSA were positively associated with VTDR.
Published: 2018

31. A genome-wide association study of corneal astigmatism: The CREAM Consortium

Author: Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, Bailey-Wilson, JE, Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, and Bailey-Wilson, JE
Abstract: PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.
Published: 2018

32. Is aspirin associated with diabetic retinopathy? The Singapore Epidemiology of Eye Disease (SEED) study.

Author: Islam, FMA, Shi, Y, Tham, Y-C, Cheung, N, Chua, J, Tan, G, Mitchell, P, Wang, JJ, Cheung, YB, Cheng, C-Y, Wong, TY, Islam, FMA, Shi, Y, Tham, Y-C, Cheung, N, Chua, J, Tan, G, Mitchell, P, Wang, JJ, Cheung, YB, Cheng, C-Y, and Wong, TY
Abstract: BACKGROUND/AIMS: To determine the association between aspirin use and diabetic retinopathy (DR) among persons with diabetes, in a population-based, cross-sectional study. METHODS: Subjects with diabetes aged >40 years from the Singapore Epidemiology of Eye Diseases Study were enrolled in this study. Retinal photographs were graded for DR according to the modified Airlie House classification system. Vision threatening diabetic retinopathy (VTDR) was defined as the presence of severe non-proliferative DR, or proliferative DR, or clinically significant macular oedema. The association between aspirin use and the presence of DR or VTDR was assessed using multivariable logistic regression models including age, gender, ethnicity, socioeconomic status, HbA1c, systolic blood pressure, anti-hypertension medicine, total cholesterol, anti-cholesterol medicine, BMI, current smoking status, diabetes duration, history of cardiovascular disease (CVD) and chronic kidney disease (CKD.). RESULTS: A total of 2,061 participants with diabetes and complete record of relevant systemic and DR data were included. Of these, 711 (34.5%) had any stage of DR, and among these 177 (8.6%) had VTDR. After adjusting for co-variables listed, the association between aspirin use and VTDR was significant (OR = 1.69, P = 0.019), while the association between aspirin use and any DR was borderline (OR = 1.31, P = 0.063). Aspirin use was not associated with either DR or VTDR after additional adjustment of CVD and CKD. Further stratification by history of CVD or CKD showed no association between aspirin use and DR/VTDR in either subgroup. CONCLUSION: Aspirin use was not significantly associated with DR but might be an indicator of diabetic complications (CVD, CKD) that were co-present with more severe DR type. Future longitudinal studies are warranted to confirm our findings.
Published: 2017

33. Joint Effects of Intraocular Pressure and Myopia on Risk of Primary Open-Angle Glaucoma: The Singapore Epidemiology of Eye Diseases Study.

Author: Tham, Y-C, Aung, T, Fan, Q, Saw, S-M, Siantar, RG, Wong, TY, Cheng, C-Y, Tham, Y-C, Aung, T, Fan, Q, Saw, S-M, Siantar, RG, Wong, TY, and Cheng, C-Y
Abstract: We examined the joint effects of intraocular pressure (IOP) and myopia on the risk of primary open angle glaucoma (POAG) in a multi-ethnic Asian population. A total of 9,422 participants (18,469 eyes) in the Singapore Epidemiology of Eye Diseases Study were included. Of them, 213 subjects (273 eyes) had POAG. All participants underwent standardised examinations. The independent and joint effects of IOP and myopia on POAG were examined using logistic regression models. Generalised estimating equation models were used to account for correlation between eyes. Higher IOP, longer axial length, and more negative spherical equivalent were independently associated with POAG, after adjusting for relevant covariates (all P ≤ 0.005). Significant interaction between IOP and myopia on POAG was observed (P interaction = 0.025). Eyes with moderate-to-high myopia (<-3.0 dioptres) with high IOP (≥20 mmHg) were 4.27 times (95% CI, 2.10-8.69) likely to have POAG, compared to eyes without myopia (>-0.5 dioptres) and with IOP <20 mmHg. Eyes with AL of ≥25.5 mm and high IOP (≥20 mmHg) were 16.22 times (95% CI, 7.73 to 34.03) likely to have POAG, compared to eyes with shorter AL (<23.5 mm) and lower IOP (<20 mmHg). These findings may provide additional insights into the pathophysiology of POAG and are particularly relevant for Asian populations.
Published: 2016

34. Aspirin and Diabetic Retinopathy: the Singapore Epidemiology of Eye Disease (SEED) study

Author: Shi, Y, Tham, Y-C, Tapp, RJ, Tan, G, Mitchell, P, Wang, JJ, Cheung, YB, Cheng, CY, Wong, TY, Shi, Y, Tham, Y-C, Tapp, RJ, Tan, G, Mitchell, P, Wang, JJ, Cheung, YB, Cheng, CY, and Wong, TY
Published: 2016

35. Association of Common SIX6 Polymorphisms With Peripapillary Retinal Nerve Fiber Layer Thickness: The Singapore Chinese Eye Study

Author: Cheng, C.-Y., primary, Allingham, R. R., additional, Aung, T., additional, Tham, Y.-C., additional, Hauser, M. A., additional, Vithana, E. N., additional, Khor, C. C., additional, and Wong, T. Y., additional
Published: 2014
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36. Detecting the optic cup excavation in retinal fundus images by automatic detection of vessel kinking

Author: Wong, D. W. K., Liu, J., Tan, N. -M, Yin, F., Lee, B. -H, Tham, Y. C., Carol Cheung, and Wong, T. Y.

37. The determination of cadmium, copper and lead in ambient air particulates in Singapore

Author: Ang, K. P., primary, Tay, B. T., additional, Gunasingham, H., additional, Teo, A. H., additional, and Tham, Y. C., additional
Published: 1988
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38. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: Yongmei Liu, Tuomas O. Kilpeläinen, Kenneth Rice, Ching-Ti Liu, Jin-Fang Chai, Donna K. Arnett, Dhananjay Vaidya, Nicholette D. Palmer, Lili Milani, Yuri Milaneschi, Leo-Pekka Lyytikäinen, Colleen M. Sitlani, Richard S. Cooper, Gudny Eiriksdottir, Daniel Levy, Jerome I. Rotter, Lihua Wang, Sven Bergmann, Yih Chung Tham, Thomas Meitinger, Lynne E. Wagenknecht, Virginia Fisher, Babatunde L. Salako, Vilmundur Gudnason, Bamidele O. Tayo, Caizheng Yu, Barry I. Freedman, Muhammad Riaz, Kaare Christensen, Ulrich Broeckel, W. James Gauderman, Massimiliano Cocca, Eric Boerwinkle, Meian He, Rob M. van Dam, M. Arfan Ikram, Lisa de las Fuentes, Jiang He, Aldi T. Kraja, Nancy L. Pedersen, Albert V. Smith, Woon-Puay Koh, Bernardo L. Horta, He Gao, Traci M. Bartz, Mike A. Nalls, Federica Laguzzi, Raymond Noordam, Paul M. Ridker, Tien Yin Wong, Patricia B. Munroe, Paul S. de Vries, Adolfo Correa, Maris Alver, Dan E. Arking, Colin A. McKenzie, John M. Starr, Chi Charles Gu, Dongfeng Gu, Stefan Weiss, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Jill M. Norris, Patrik K. E. Magnusson, Tamar Sofer, Ioanna Ntalla, Xiuqing Guo, Paul Elliott, Lawrence F. Bielak, Konstantin Strauch, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Ilja M. Nolte, Steven C. Hunt, Mario Sims, Giorgia Girotto, Chuan Gao, Pamela J. Schreiner, Philippe Froguel, Archie Campbell, Xiao-Ou Shu, Claude Bouchard, Kurt Lohman, David R. Weir, José Eduardo Krieger, Yii-Der Ida Chen, Rainer Rauramaa, Walter Palmas, Cornelia M. van Duijn, James M. Shikany, Michael M. Province, Jennifer A. Smith, Wei Zheng, Xiaofeng Zhu, Jianjun Liu, Ozren Polasek, Alexandre C. Pereira, Diane M. Becker, Kari E. North, Salman M. Tajuddin, Deng Xuan, Leslie J. Raffel, Jie Yao, Astrid Petersmann, Ervin F. Fox, Mark J. Caulfield, Daniel I. Chasman, Jasmin Divers, Claudia P. Cabrera, Rico Rueedi, M. Yldau van der Ende, Carl D. Langefeld, Mika Kähönen, Terrence Forrester, Tangchun Wu, Harold Snieder, Caroline Hayward, Tamara B. Harris, Fang-Chi Hsu, Helen R. Warren, Brenda W.J.H. Penninx, Chiea Chuen Khor, Ruifang Li-Gao, Changwei Li, Sami Heikkinen, Jeffrey R. O'Connell, Christian Gieger, Michele K. Evans, Ching-Yu Cheng, Jingjing Liang, Stephen B. Kritchevsky, Gregory L. Burke, Donald W. Bowden, Alexander Teumer, Marcus Dörr, Alanna C. Morrison, Jian-Min Yuan, Annette Peters, Dennis O. Mook-Kanamori, Pedro Marques-Vidal, Pirjo Komulainen, Lisa R. Yanek, Melanie Waldenberger, Alisa K. Manning, Charles N. Rotimi, Chew-Kiat Heng, Tõnu Esko, Franco Giulianini, Miao Li Chee, Treva Rice, David J. Porteous, Yechiel Friedlander, Bing Yu, Myriam Fornage, Karin Leander, Dina Vojinovic, Sharon L.R. Kardia, Xiaoyin Li, Najaf Amin, Karen Schwander, Thomas T. Perls, Oscar Leonel Rueda-Ochoa, Erin B. Ware, Ya Xing Wang, Sandosh Padmanabhan, H. Janaka de Silva, André G. Uitterlinden, Rajkumar Dorajoo, Bruna Gigante, Jennifer A. Brody, Paolo Gasparini, Maryam Kavousi, Wanqing Wen, Stephen Sidney, Alan B. Zonderman, Michael R. Brown, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Alaitz Poveda, Bruce M. Psaty, Terho Lehtimäki, Tanika N. Kelly, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, John M. C. Connell, Mickaël Canouil, Niek Verweij, Thomas W. Winkler, Ian J. Deary, Marco Brumat, Yize Li, Fumihiko Takeuchi, Wei Zhao, Andres Metspalu, Marguerite R. Irvin, David C. Liewald, Pim van der Harst, Hugues Aschard, Candace M. Kammerer, Melissa A. Richard, Adesola Ogunniyi, Wen Bin Wei, Morris A. Swertz, Fernando Pires Hartwig, Dabeeru C. Rao, Reedik Mägi, Solomon K. Musani, Mathilde Boissel, Jonathan Marten, Nilesh J. Samani, Amy R. Bentley, Sarah E. Harris, Charumathi Sabanayagam, Mary F. Feitosa, Jost B. Jonas, Andrea R. V. R. Horimoto, Paul W. Franks, E. Shyong Tai, Medical Research Council (MRC), de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., Bentley, A. R., Brown, M. R., Guo, X., Manning, A., Chasman, D. I., Aschard, H., Bartz, T. M., Bielak, L. F., Campbell, A., Cheng, C. -Y., Dorajoo, R., Hartwig, F. P., Horimoto, A. R. V. R., Li, C., Li-Gao, R., Liu, Y., Marten, J., Musani, S. K., Ntalla, I., Rankinen, T., Richard, M., Sim, X., Smith, A. V., Tajuddin, S. M., Tayo, B. O., Vojinovic, D., Warren, H. R., Xuan, D., Alver, M., Boissel, M., Chai, J. -F., Chen, X., Christensen, K., Divers, J., Evangelou, E., Gao, C., Girotto, G., Harris, S. E., He, M., Hsu, F. -C., Kuhnel, B., Laguzzi, F., Li, X., Lyytikainen, L. -P., Nolte, I. M., Poveda, A., Rauramaa, R., Riaz, M., Rueedi, R., Shu, X. -O., Snieder, H., Sofer, T., Takeuchi, F., Verweij, N., Ware, E. B., Weiss, S., Yanek, L. R., Amin, N., Arking, D. E., Arnett, D. K., Bergmann, S., Boerwinkle, E., Brody, J. A., Broeckel, U., Brumat, M., Burke, G., Cabrera, C. P., Canouil, M., Chee, M. L., Chen, Y. -D. I., Cocca, M., Connell, J., de Silva, H. J., de Vries, P. S., Eiriksdottir, G., Faul, J. D., Fisher, V., Forrester, T., Fox, E. F., Friedlander, Y., Gao, H., Gigante, B., Giulianini, F., Gu, C. C., Gu, D., Harris, T. B., He, J., Heikkinen, S., Heng, C. -K., Hunt, S., Ikram, M. A., Irvin, M. R., Kahonen, M., Kavousi, M., Khor, C. C., Kilpelainen, T. O., Koh, W. -P., Komulainen, P., Kraja, A. T., Krieger, J. E., Langefeld, C. D., Li, Y., Liang, J., Liewald, D. C. M., Liu, C. -T., Liu, J., Lohman, K. K., Magi, R., Mckenzie, C. A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mook-Kanamori, D. O., Nalls, M. A., Nelson, C. P., Norris, J. M., O'Connell, J., Ogunniyi, A., Padmanabhan, S., Palmer, N. D., Pedersen, N. L., Perls, T., Peters, A., Petersmann, A., Peyser, P. A., Polasek, O., Porteous, D. J., Raffel, L. J., Rice, T. K., Rotter, J. I., Rudan, I., Rueda-Ochoa, O. -L., Sabanayagam, C., Salako, B. L., Schreiner, P. J., Shikany, J. M., Sidney, S. S., Sims, M., Sitlani, C. M., Smith, J. A., Starr, J. M., Strauch, K., Swertz, M. A., Teumer, A., Tham, Y. C., Uitterlinden, A. G., Vaidya, D., van der Ende, M. Y., Waldenberger, M., Wang, L., Wang, Y. -X., Wei, W. -B., Weir, D. R., Wen, W., Yao, J., Yu, B., Yu, C., Yuan, J. -M., Zhao, W., Zonderman, A. B., Becker, D. M., Bowden, D. W., Deary, I. J., Dorr, M., Esko, T., Freedman, B. I., Froguel, P., Gasparini, P., Gieger, C., Jonas, J. B., Kammerer, C. M., Kato, N., Lakka, T. A., Leander, K., Lehtimaki, T., Magnusson, P. K. E., Marques-Vidal, P., Penninx, B. W. J. H., Samani, N. J., van der Harst, P., Wagenknecht, L. E., Wu, T., Zheng, W., Zhu, X., Bouchard, C., Cooper, R. S., Correa, A., Evans, M. K., Gudnason, V., Hayward, C., Horta, B. L., Kelly, T. N., Kritchevsky, S. B., Levy, D., Palmas, W. R., Pereira, A. C., Province, M. M., Psaty, B. M., Ridker, P. M., Rotimi, C. N., Tai, E. S., van Dam, R. M., van Duijn, C. M., Wong, T. Y., Rice, K., Gauderman, W. J., Morrison, A. C., North, K. E., Kardia, S. L. R., Caulfield, M. J., Elliott, P., Munroe, P. B., Franks, P. W., Rao, D. C., Fornage, M., Washington University in Saint Louis (WUSTL), Leiden University Medical Center (LUMC), University of Regensburg, Washington University School of Medicine in St. Louis, National Institutes of Health [Bethesda] (NIH), Harbor UCLA Medical Center [Torrance, Ca.], Massachusetts General Hospital [Boston], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Lifelines Cohort Study, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Cardiovascular Centre (CVC)
Subjects: 0301 basic medicine, CORONARY-HEART-DISEASE, SOCIOECONOMIC-STATUS, RISK-FACTORS, CARDIOVASCULAR-DISEASE, ESSENTIAL-HYPERTENSION, C825T POLYMORPHISM, SOCIAL-CLASS, ASSOCIATION, EXPRESSION, VARIANTS, Blood Pressure, Genome, 0302 clinical medicine, 11 Medical and Health Sciences, Genetics, Psychiatry, [STAT.AP]Statistics [stat]/Applications [stat.AP], 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Meta-analysis, Hypertension, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, GNB3, Biochemistry & Molecular Biology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Humans, Risk factor, Molecular Biology, Gene, Science & Technology, Neurosciences, Epistasis, Genetic, 06 Biological Sciences, Genetic architecture, Educational attainment, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Blood Pressure/genetics, Genome-Wide Association Study, Hypertension/genetics, 030217 neurology & neurosurgery
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2020
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39. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019
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