ORCID Profile
0000-0002-8944-1771
Current Organisations
University of Oxford
,
Erasmus MC
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Publisher: Oxford University Press (OUP)
Date: 28-10-2017
DOI: 10.1093/HMG/DDX390
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: Public Library of Science (PLoS)
Date: 12-06-2014
Publisher: European Respiratory Society (ERS)
Date: 05-12-2013
DOI: 10.1183/09031936.00046213
Abstract: Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interin idual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 in iduals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= -0.0452, p=0.024) as well as COPD (β= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
Publisher: Springer Science and Business Media LLC
Date: 12-06-2015
DOI: 10.1038/NCOMMS8208
Publisher: Springer Science and Business Media LLC
Date: 26-04-2017
DOI: 10.1038/NCOMMS14977
Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study s le. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
Publisher: Public Library of Science (PLoS)
Date: 18-03-2015
Publisher: Springer Science and Business Media LLC
Date: 04-05-2016
DOI: 10.1038/EJHG.2016.31
Publisher: Springer Science and Business Media LLC
Date: 10-2018
Publisher: Oxford University Press (OUP)
Date: 07-03-2013
DOI: 10.1093/HMG/DDT116
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1038/NG.3698
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
DOI: 10.1038/S41598-019-47282-6
Abstract: Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 in iduals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological s les from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10 −6 ), methionine ( p-value = 9.2 × 10 −5 ), tyrosine ( p-value = 2.1 × 10 −4 ), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10 −4 ), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10 −4 ), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10 −4 ). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2015
DOI: 10.1038/MP.2015.37
Publisher: Springer Science and Business Media LLC
Date: 26-06-2011
DOI: 10.1038/NG.866
Publisher: Wiley
Date: 28-01-2015
DOI: 10.1002/GEPI.21886
Publisher: Springer Science and Business Media LLC
Date: 05-06-2012
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NATURE14878
Publisher: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1038/NATURE13545
Publisher: Elsevier BV
Date: 07-2014
Publisher: Elsevier BV
Date: 02-2010
Publisher: Springer Science and Business Media LLC
Date: 30-03-2011
DOI: 10.1038/EJHG.2011.21
Publisher: Oxford University Press (OUP)
Date: 30-01-2015
DOI: 10.1093/HMG/DDV027
Abstract: Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9) for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-712B
Publisher: Proceedings of the National Academy of Sciences
Date: 08-01-2015
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NCOMMS10494
Abstract: Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin ( LEP ) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 in iduals and followed up loci reaching P −6 in 19,979 additional in iduals. We identify five loci robustly associated ( P × 10 −8 ) with leptin levels in/near LEP , SLC32A1 , GCKR , CCNL1 and FTO . Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin , a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2237
Publisher: Springer Science and Business Media LLC
Date: 21-12-2010
DOI: 10.1038/MP.2010.128
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1093/AJCN/NQY272
Publisher: Springer Science and Business Media LLC
Date: 05-12-2012
Publisher: Springer Science and Business Media LLC
Date: 10-01-2017
DOI: 10.1038/MP.2016.231
Publisher: Public Library of Science (PLoS)
Date: 03-05-2012
Publisher: Public Library of Science (PLoS)
Date: 07-08-2014
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 18-01-2017
DOI: 10.1038/NCOMMS13624
Abstract: The hippoc al formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippoc al volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippoc al structure here we perform a genome-wide association study (GWAS) of 33,536 in iduals and discover six independent loci significantly associated with hippoc al volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2 , DPP4 and MAST4 ) and one is found 200 kb upstream of SHH . A hippoc al subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippoc al volume are also associated with increased risk for Alzheimer’s disease ( r g =−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippoc al volume and risk for neuropsychiatric illness.
Publisher: Wiley
Date: 05-07-2014
DOI: 10.1002/AJMG.B.32254
Abstract: The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent s le of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2016
DOI: 10.1038/NG.3552
Publisher: Springer Science and Business Media LLC
Date: 16-01-2013
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/NATURE17671
Publisher: Springer Science and Business Media LLC
Date: 08-02-2018
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Springer Science and Business Media LLC
Date: 18-10-2011
DOI: 10.1038/TP.2011.45
Publisher: Public Library of Science (PLoS)
Date: 11-2011
Publisher: Springer Science and Business Media LLC
Date: 30-08-2011
DOI: 10.1038/MP.2011.101
Publisher: Public Library of Science (PLoS)
Date: 27-04-2017
Publisher: Springer Science and Business Media LLC
Date: 22-09-2014
DOI: 10.1038/NCOMMS5883
Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 in iduals of European ancestry and 6,784 in iduals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-2013
Abstract: Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 s les, Rietveld et al. (p. 1467 , published online 30 May see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Springer Science and Business Media LLC
Date: 30-03-2011
DOI: 10.1038/EJHG.2011.48
Publisher: Oxford University Press (OUP)
Date: 22-03-2011
DOI: 10.1093/HMG/DDR120
Abstract: Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), South ton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NG.3667
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Public Library of Science (PLoS)
Date: 10-06-2010
Publisher: Proceedings of the National Academy of Sciences
Date: 08-09-2014
Abstract: We identify several common genetic variants associated with cognitive performance using a two-stage approach: we conduct a genome-wide association study of educational attainment to generate a set of candidates, and then we estimate the association of these variants with cognitive performance. In older Americans, we find that these variants are jointly associated with cognitive health. Bioinformatics analyses implicate a set of genes that is associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. In addition to the substantive contribution, this work also serves to show a proxy-phenotype approach to discovering common genetic variants that is likely to be useful for many phenotypes of interest to social scientists (such as personality traits).
Publisher: Elsevier BV
Date: 03-2009
Publisher: Hindawi Limited
Date: 09-06-2017
DOI: 10.1002/HUMU.23247
Abstract: Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10
Publisher: Springer Science and Business Media LLC
Date: 19-07-2017
DOI: 10.1038/S41467-017-00031-7
Abstract: Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass ( n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide ( p 5 × 10 −8 ) or suggestively genome wide ( p 2.3 × 10 −6 ). Replication in 63,475 (47,227 of European ancestry) in iduals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3 , IRS1 , and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN , ADAMTSL3 , and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
Publisher: Springer Science and Business Media LLC
Date: 04-2022
DOI: 10.1038/S41588-022-01024-Z
Abstract: Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Publisher: Wiley
Date: 19-12-2014
Publisher: Springer Science and Business Media LLC
Date: 16-08-2200
DOI: 10.1038/S41380-022-01710-8
Abstract: Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke ( N = 53,637). We identified novel loci in the intronic region of CDH18 , and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent s le. Functional and bioinformatic analyses supported many of these loci and further implicated POC1 . We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Public Library of Science (PLoS)
Date: 22-12-2015
Publisher: Proceedings of the National Academy of Sciences
Date: 06-04-2011
Abstract: Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based s les of European ancestry, comprising 26,316 in iduals, with replication genotyping in an additional 21,185 in iduals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex s les ( P = 0.026) and significant ( P 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2015
DOI: 10.1038/NG.3412
Publisher: Springer Science and Business Media LLC
Date: 22-06-2010
DOI: 10.1038/MP.2010.65
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
Publisher: IEEE
Date: 11-2013
Publisher: Springer Science and Business Media LLC
Date: 17-07-2017
DOI: 10.1038/NG.3916
Publisher: American Thoracic Society
Date: 15-11-2016
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NG.663
Publisher: Public Library of Science (PLoS)
Date: 18-09-2014
Publisher: Proceedings of the National Academy of Sciences
Date: 13-05-2011
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1038/MP.2014.188
Abstract: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts ( N =53 949) in which the participants had undertaken multiple, erse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P =3.93 × 10 −9 , MIR2113 rs17522122, P =2.55 × 10 −8 , AKAP6 rs10119, P =5.67 × 10 −9 , APOE/TOMM40 ). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 ( P =1 × 10 −6 ). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study ( N =6617) and the Health and Retirement Study ( N =5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort ( N =5487 P =1.5 × 10 −17 ). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40 , APOE , ABCG1 and MEF2C .
Publisher: Elsevier BV
Date: 09-2017
Publisher: Oxford University Press (OUP)
Date: 10-01-2017
DOI: 10.1093/HMG/DDW399
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
DOI: 10.1038/NG.3087
Publisher: Wiley
Date: 30-03-2016
DOI: 10.1002/ANA.24621
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
DOI: 10.1161/HYPERTENSIONAHA.117.09438
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry in iduals and sought significant evidence for independent replication in a further 228 245 in iduals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 in iduals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NG.2554
Publisher: Springer Science and Business Media LLC
Date: 07-10-2014
DOI: 10.1038/MP.2014.107
Publisher: Springer Science and Business Media LLC
Date: 23-06-2013
DOI: 10.1038/NG.2676
Publisher: Springer Science and Business Media LLC
Date: 30-01-2017
DOI: 10.1038/NG.3768
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 17-03-2015
DOI: 10.1038/MP.2015.23
Publisher: Springer Science and Business Media LLC
Date: 25-04-2010
DOI: 10.1038/NG.573
Publisher: Elsevier BV
Date: 07-2014
Publisher: Public Library of Science (PLoS)
Date: 06-06-2013
Publisher: Public Library of Science (PLoS)
Date: 19-07-2012
Publisher: Springer Science and Business Media LLC
Date: 18-01-2019
DOI: 10.1007/S10519-018-09947-2
Abstract: We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 in iduals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753 p-value = 3.02 × 10
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1038/NCOMMS11008
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry in iduals, we identify six novel loci ( FAM150B-ACP1 , LINC00340 , FBN1 , DIS3L-MAP2K1 , ARID2-SNAT1 and SLC14A2 ) associated with refractive error. In Asian populations, three genome-wide significant loci AREG , GABRR1 and PDE10A also exhibit strong interactions with education ( P .5 × 10 −5 ), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Publisher: Springer Science and Business Media LLC
Date: 27-06-2010
DOI: 10.1038/NG.609
Publisher: Springer Science and Business Media LLC
Date: 07-03-2019
Publisher: Springer Science and Business Media LLC
Date: 27-10-2013
DOI: 10.1038/NG.2802
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1161/CIRCGENETICS.116.001572
Abstract: The burden of subclinical atherosclerosis in asymptomatic in iduals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77 P =1×10 − 11 ). Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2009
DOI: 10.1038/NG.446
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JACI.2016.06.062
Abstract: Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group exclusively. The aim of this study was to identify common genetic variants associated with FEV Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results (P < 10 We identified associations between the FEV The genes HHIP and FAM13A confer a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease.
Publisher: Elsevier BV
Date: 06-2015
Publisher: Public Library of Science (PLoS)
Date: 26-06-2009
Publisher: Springer Science and Business Media LLC
Date: 12-07-2017
DOI: 10.1038/NCOMMS16015
Abstract: Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined s le of 195,180 in iduals and identify 16 loci associated with grip strength ( P × 10 −8 ) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres ( ACTG1 ), neuronal maintenance and signal transduction ( PEX14, TGFA, SYT1 ), or monogenic syndromes with involvement of psychomotor impairment ( PEX14, LRPPRC and KANSL1 ). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Springer Science and Business Media LLC
Date: 21-11-2010
DOI: 10.1038/NG.714
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Najaf Amin.