The Rotterdam Study: 2010 objectives and design update

Hofman, Albert; Breteler, Monique M.B.; Duijn, Cornelia M. van; Janssen, Harry L.A.; Krestin, Gabriël P.; Kuipers, Ernst J.; Stricker, Bruno H. Ch.; Tiemeier, Henning; Uitterlinden, André G.; Vingerling, Johannes R.; Witteman, Jacqueline C. M.

doi:10.1007/s10654-009-9386-z

Cited by 247 publications

(210 citation statements)

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“…After QC, a total of 772 Dutch PD cases and 2024 controls from the Rotterdam study [12][13][14] genotyped in a total of 514 799 unique autosomal SNPs, were included in our analyses (Table 1). To assess the homogeneity of our cohort, identity by state (IBS) distances were calculated.…”

Section: Resultsmentioning

confidence: 99%

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Genome-wide association study confirms extant PD risk loci among the Dutch

et al. 2011

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Section: Resultsmentioning

confidence: 99%

“…Genome-wide genotyping data from 2082 control participants from the Rotterdam study III [12][13][14] (ERGO Young) genotyped with Human610K beadchips from Illumina (http://www.illumina.com) were used as our control population. Of these, 912 were males and 1116 females.…”

Section: Subjects and Methods Subjectsmentioning

confidence: 99%

Genome-wide association study confirms extant PD risk loci among the Dutch

et al. 2011

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“…The association of serum TSH and FT 4 levels with genetic variation in the candidate genes was studied in the Rotterdam Study (22). Promising associations were studied in a Danish twin population (6), the Scan Study (23), and the Nijmegen Biomedical Study (24) for confirmation, after which a meta-analysis of all four studies was conducted.…”

Section: Methodsmentioning

confidence: 99%

A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels

Medici¹,

Deure²,

Verbiest³

et al. 2011

European Journal of Endocrinology

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Objective: Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT 4 ) levels. Design and methods: Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT 4 levels in 1121 Caucasian subjects. Promising hits (P!0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed. Results: For TSH, eight PDE8B polymorphisms (PZ4!10 K17 ) remained significant in the metaanalysis. For FT 4 , two DIO1 (PZ8!10 K12 ) and one FOXE1 (PZ0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (PZ0.0028) and three THRB (PZ0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (PZ0.0110) with FT 4 , but failed to reach the significant multiple-testing corrected P value (P!0.0022 and P!0.0033 respectively). Conclusions: Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT 4 levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT 4 levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.

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“…RS-II, which was not a part of the ENGAGE discovery set, consists of 3011 participants (out of 4472 invitees) who were 55 years or older during the recruitment period (2000)(2001). 20 Of the 3011, 2540 persons were successfully genotyped with an Illumina 610K array. Fasting HDL-C, TG and TC were measured with enzymatic colorimetric tests on a Roche/Hitachi 911 analyzer (Roche Diagnostics, Meylan, France).…”

Section: Methodsmentioning

confidence: 99%

Genetic architecture of circulating lipid levels

et al. 2011

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for the ENGAGE CONSORTIUM Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

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The Rotterdam Study: 2010 objectives and design update

Cited by 247 publications

References 246 publications

Genome-wide association study confirms extant PD risk loci among the Dutch

Genome-wide association study confirms extant PD risk loci among the Dutch

A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels

Genetic architecture of circulating lipid levels

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