| 1. |
- Machiela, Mitchell J., et al.
(author)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Journal article (peer-reviewed)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 2. |
- Qi, Qibin, et al.
(author)
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FTO genetic variants, dietary intake and body mass index : insights from 177 330 individuals
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:25, s. 6961-6972
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Journal article (peer-reviewed)abstract
- FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
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| 3. |
- Kim, Jihye, et al.
(author)
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Association of coffee, tea, and caffeine consumption with intraocular pressure and interaction with genetic risk : findings from the UK Biobank
- 2020
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In: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology. - 0146-0404 .- 1552-5783. ; 61:7
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Journal article (other academic/artistic)abstract
- Purpose : Coffee and tea are commonly consumed caffeinated beverages that may affect ocular health. Hence, it is of interest whether caffeine intake affects intraocular pressure (IOP). Some studies reported that coffee and caffeine consumption is associated with higher IOP. However, evidence from large-scale general population studies is limited. Methods : We included 121,755 UK Biobank participants (aged 39-73y) who had dietary data and cornea-compensated IOP measurements in 2006-2010. In a subset (n=78,017), data were available from up to five web-based 24-hour-recall food frequency questionnaires (2009-2012); we derived participants’ total caffeine consumption based on caffeine content and frequency of caffeine-containing food intake. Using multivariable linear regression, we assessed the cross-sectional relationships between coffee or tea intake (cups/day) and IOP (mmHg) as primary analyses and the associations between total caffeine intake (80 mg/day) and IOP (mmHg) as secondary analyses. Analyses were adjusted for age, sex, ethnicity, smoking, alcohol intake, physical activity, deprivation, body mass index, blood pressure, and diabetes (and total energy intake in the subset). To explore gene-diet interactions, we examined interactions between coffee, tea, caffeine intake and an IOP polygenic risk score (PRS) combining effects of 111 genetic variants associated with IOP identified by genome-wide association studies. Results : Mean (SD) IOP was 16.0 (3.8) mmHg. Higher coffee, tea, and total caffeine intakes were associated with lower IOP (-0.049, -0.045 and -0.039 mmHg, respectively; P ≤ 0.001). When evaluating PRS-diet interactions, we found positive and significant interactions with tea and caffeine intake (both P-interactions < 0.05), where higher tea and caffeine intake was associated with lower IOP among individuals with IOP PRS in the lower 75th percentile, while among individuals with high IOP PRS (top 25th percentile), higher intakes were associated with modestly higher IOP. Conclusions : We found evidence for very weak associations between higher coffee, tea and caffeine intake and lower IOP. However, our finding on gene-diet interactions suggest that genetic predisposition to higher IOP may influence the association between caffeinated beverage consumption and IOP.
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| 4. |
- Kim, Jihye, et al.
(author)
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Intraocular pressure, glaucoma and dietary caffeine consumption : a gene-diet interaction study from the UK Biobank
- 2021
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In: Ophthalmology. - : Elsevier. - 0161-6420 .- 1549-4713. ; 128:6, s. 866-876
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Journal article (peer-reviewed)abstract
- Purpose: We examined the association of habitual caffeine intake with intraocular pressure (IOP) and glaucoma and whether genetic predisposition to higher IOP modified these associations. We also assessed whether genetic predisposition to higher coffee consumption was related to IOP.Design: Cross-sectional study in the UK Biobank.Participants: We included 121 374 participants (baseline ages, 39-73 years) with data on coffee and tea intake (collected 2006-2010) and corneal-compensated IOP measurements in 2009. In a subset of 77 906 participants with up to 5 web-based 24-hour-recall food frequency questionnaires (2009-2012), we evaluated total caffeine intake. We also assessed the same relationships with glaucoma (9286 cases and 189 763 controls).Methods: We evaluated multivariable-adjusted associations with IOP using linear regression and with glaucoma using logistic regression. For both outcomes, we examined gene-diet interactions using a polygenic risk score (PRS) that combined the effects of 111 genetic variants associated with IOP. We also performed Mendelian randomization using 8 genetic variants associated with coffee intake to assess potential causal effects of coffee consumption on IOP.Main Outcome Measures: Intraocular pressure and glaucoma.Results: Mendelian randomization analysis did not support a causal effect of coffee drinking on IOP (P > 0.1). Greater caffeine intake was associated weakly with lower IOP: the highest (>= 232 mg/day) versus lowest (<87 mg/day) caffeine consumption was associated with a 0.10-mmHg lower IOP (P-trend = 0.01). However, the IOP PRS modified this association: among those in the highest IOP PRS quartile, consuming > 480 mg/day versus < 80 mg/day was associated with a 0.35-mmHg higher IOP (P-interaction = 0.01). The relationship between caffeine intake and glaucoma was null (P >= 0.1). However, the IOP PRS also modified this relationship: compared with those in the lowest IOP PRS quartile consuming no caffeine, those in the highest IOP PRS quartile consuming >= 321 mg/day showed a 3.90-fold higher glaucoma prevalence (P-interaction = 0.0003).Conclusions: Habitual caffeine consumption was associated weakly with lower IOP, and the association between caffeine consumption and glaucoma was null. However, among participants with the strongest genetic predisposition to elevated IOP, greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence.
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| 5. |
- Madjedi, Kian M., et al.
(author)
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The Association between Serum Lipids and Intraocular Pressure in 2 Large United Kingdom Cohorts
- 2022
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In: Ophthalmology. - : Elsevier. - 0161-6420 .- 1549-4713. ; 129:9, s. 986-996
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Journal article (peer-reviewed)abstract
- PURPOSE: Serum lipids are modifiable, routinely collected blood tests associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL-C) and triglycerides (TG)) with intraocular pressure (IOP).DESIGN: Cross-sectional study in the UK Biobank and EPIC-Norfolk cohorts.PARTICIPANTS: We included 94 323 participants of UK Biobank (mean age 57 years) and 6 230 participants of EPIC-Norfolk (mean age 68 years) with data on TC, HDL-C, LDL-C, TG collected between 2006-2009.METHODS: Multivariable linear regression adjusting for demographic, lifestyle, anthropometric, medical and ophthalmic covariables was used to examine the associations of serum lipids with IOPcc.MAIN OUTCOME MEASURES: IOPcc.RESULTS: Higher levels of TC, HDL-C and LDL-C were independently associated with higher IOPcc in both cohorts after adjustment for key demographic, medical and lifestyle factors. For each standard deviation increase in TC, HDL-C, and LDL-C, IOPcc (mmHg) was higher by 0.09 (95% CI: 0.06-0.11; P<0.001), 0.11 (95% CI 0.08-0.13; P<0.001), 0.07 (95% CI: 0.05-0.09, P<0.001), respectively in the UK Biobank cohort. In the EPIC-Norfolk cohort, each additional standard deviation in TC, HDL-C, and LDL-C was associated with a higher IOPcc (mmHg) by 0.19 (95% CI 0.07-0.31, P=0.001), 0.14 (95% CI 0.03-0.25, P=0.016), and 0.17 (95% CI 0.06-0.29, P=0.003). An inverse association between TGs and IOP in the UK Biobank (-0.05, 95% CI -0.08 to -0.03, P<0.001) was not replicated in the EPIC cohort (P=0.30).CONCLUSION: Our findings suggest that serum TC, HDL-C and LDL-C are positively associated with IOP in two UK cohorts and TGs may be negatively associated. Future research is required to assess whether these associations are causal in nature.
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| 6. |
- Stuart, Kelsey V., et al.
(author)
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The association of alcohol consumption with glaucoma and related traits : findings from the UK Biobank
- 2023
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In: Ophthalmology Glaucoma. - : Elsevier. - 2589-4234 .- 2589-4196. ; 6:4, s. 366-379
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Journal article (peer-reviewed)abstract
- PURPOSE: To examine the associations of alcohol consumption with glaucoma and related traits; to assess whether a genetic predisposition to glaucoma modified these associations; and to perform Mendelian randomization (MR) experiments to probe causal effects.DESIGN: Cross-sectional observational and gene-environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia.PARTICIPANTS: UK Biobank participants with data on intraocular pressure (IOP) (n=109 097), OCT derived macular inner retinal layer thickness measures (n=46 236) and glaucoma status (n=173 407).METHODS: Participants were categorized according to self-reported drinking behaviors. Quantitative estimates of alcohol intake were derived from touchscreen questionnaires and food composition tables. We performed a two-step analysis, first comparing categories of alcohol consumption (never, infrequent, regular, and former drinkers), before assessing for a dose-response effect in regular drinkers only. Multivariable linear, logistic and restricted cubic spline (RCS) regression, adjusted for key sociodemographic, medical, anthropometric and lifestyle factors, were used to examine associations. We assessed whether any association was modified by a multi-trait glaucoma polygenic risk score. The inverse-variance weighted method was used for the main MR analyses.MAIN OUTCOME MEASURES: IOP, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and prevalent glaucoma. RESULTS: Compared to infrequent drinkers, regular drinkers had higher IOP (+0.17mmHg; P<0.001) and thinner mGCIPL (-0.17μm; P=0.049); while former drinkers had a higher prevalence of glaucoma (OR 1.53; P=0.002). In regular drinkers, alcohol intake was adversely associated with all outcomes in a dose-dependent manner (all P<0.001). RCS regression analyses suggested non-linear associations, with apparent threshold effects at approximately 50g (∼6 UK or 4 US alcoholic units)/week, for mRNFL and mGCIPL thickness. Significantly stronger alcohol-IOP associations were observed in participants at higher genetic susceptibility to glaucoma (Pinteraction<0.001). MR analyses provided evidence for a causal association with mGCIPL thickness.CONCLUSIONS: Alcohol intake was consistently and adversely associated with glaucoma and related traits, and at levels below current UK (<112g/week) and US (women: <98g/week; men: <196g/week) guidelines. While we cannot infer causality definitively, these results will be of interest to people with, or at risk of, glaucoma and their advising physicians.
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