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1. Somatic TARDBP variants as a cause of semantic dementia

Author

Rooij, J.G.J. (Jeroen) van, Mol, M.O., Melhem, S. (Shamiram), van der Wal, P. (Pelle), Arp, P.P. (Pascal), Paron, F. (Francesca), Donker Kaat, L. (Laura), Seelaar, H. (Harro), Miedema, S.S.M. (Suzanne S M), Oshima, T. (Takuya), Eggen, B.J.L. (Bart J L), Uitterlinden, A.G. (André), van Meurs, J. (Joyce), Kesteren, R.E. (Ronald) van, Smit, A.B. (August), Buratti, E. (Emanuele), Swieten, J.C. (John) van, Rooij, J.G.J. (Jeroen) van, Mol, M.O., Melhem, S. (Shamiram), van der Wal, P. (Pelle), Arp, P.P. (Pascal), Paron, F. (Francesca), Donker Kaat, L. (Laura), Seelaar, H. (Harro), Miedema, S.S.M. (Suzanne S M), Oshima, T. (Takuya), Eggen, B.J.L. (Bart J L), Uitterlinden, A.G. (André), van Meurs, J. (Joyce), Kesteren, R.E. (Ronald) van, Smit, A.B. (August), Buratti, E. (Emanuele), and Swieten, J.C. (John) van

Abstract

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in

Published
2020
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2. Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time

Author

Rooij, J.G.J. (Jeroen) van, Arp, P.P. (Pascal), Broer, L. (Linda), Verlouw, J.A.M. (Joost), Rooij, F.J.A. (Frank) van, Kraaij, R. (Robert), Uitterlinden, A.G. (André), Verkerk, A., Rooij, J.G.J. (Jeroen) van, Arp, P.P. (Pascal), Broer, L. (Linda), Verlouw, J.A.M. (Joost), Rooij, F.J.A. (Frank) van, Kraaij, R. (Robert), Uitterlinden, A.G. (André), and Verkerk, A.

Abstract

Purpose: We studied the penetrance of pathogenically classified variants in an elderly Dutch population from the Rotterdam Study, for which deep phenotyping is available. We screened the 59 actionable genes for which reporting of known pathogenic variants was recommended by the American College of Medical Genetics and Genomics (ACMG), and demonstrate that determining what constitutes a known pathogenic variant can be quite challenging. Methods: We defined “known pathogenic” as classified pathogenic by both ClinVar and the Human Gene Mutation Database (HGMD). In 2628 individuals, we performed exome sequencing and identified known pathogenic variants. We investigated the clinical records of carriers and evaluated clinical events during 25 years of follow-up for evidence of variant pathogenicity. Results: Of 3815 variants detected in the 59 ACMG genes, 17 variants were considered known pathogenic. For 14/17 variants the ClinVar classification had changed over time. Of 24 confirmed carriers of these variants, we observed at least one clinical event possibly caused by the variant in only three participants (13%). Conclusion: We show that the definition of “known pathogenic” is often unclea

Published
2020
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3. Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length

Author

Spek, A. (Ashley) van der, Warner, S.C. (Sophie C.), Broer, L. (Linda), Nelson, C.P. (Christopher), Vojinović, D. (Dina), Ahmad, S. (Shahzad), Arp, P.P. (Pascal), Brouwer, R.W.W. (Rutger), Denniff, M. (Matthew), van den hout, M.C.G.N. (Mirjam), Rooij, J.G.J. (Jeroen) van, Kraaij, R. (Robert), IJcken, W.F.J. (Wilfred) van, Samani, N.J. (Nilesh), Ikram, M.A. (Arfan), Uitterlinden, A.G. (André), Codd, V. (Veryan), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Spek, A. (Ashley) van der, Warner, S.C. (Sophie C.), Broer, L. (Linda), Nelson, C.P. (Christopher), Vojinović, D. (Dina), Ahmad, S. (Shahzad), Arp, P.P. (Pascal), Brouwer, R.W.W. (Rutger), Denniff, M. (Matthew), van den hout, M.C.G.N. (Mirjam), Rooij, J.G.J. (Jeroen) van, Kraaij, R. (Robert), IJcken, W.F.J. (Wilfred) van, Samani, N.J. (Nilesh), Ikram, M.A. (Arfan), Uitterlinden, A.G. (André), Codd, V. (Veryan), Amin, N. (Najaf), and Duijn, C.M. (Cornelia) van

Abstract

Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10–7, minor allele frequency of 0.2–0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10−6), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10–4) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.

Published
2020
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4. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author

Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), Codd, V. (Veryan), Li, C. (Chen), Stoma, S. (Svetlana), Lotta, L.A. (Luca A.), Warner, S. (Sophie), Albrecht, E. (Eva), Allione, A. (Alessandra), Arp, P.P. (Pascal), Broer, L. (Linda), Buxton, J.L. (Jessica L.), Da Silva Couto Alves, A. (Alexessander), Deelen, J. (Joris), Fedko, I.O. (Iryna O.), Gordon, S.D. (Scott D.), Jiang, T. (Tao), Karlsson, R. (Robert), Kerrison, N. (Nicola), Loe, T.K. (Taylor K.), Mangino, M. (Massimo), Milaneschi, Y. (Yuri), Miraglio, B. (Benjamin), Pervjakova, N. (Natalia), Russo, A. (Alessia), Surakka, I. (Ida), Spek, A. (Ashley) van der, Verhoeven, J.E. (Josine E.), Amin, N. (Najaf), Beekman, M. (Marian), Blakemore, A.I. (Alexandra I.), Canzian, F. (Federico), Hamby, S.E. (Stephen E.), Hottenga, J.J. (Jouke Jan), Jones, P.D. (Peter D.), Jousilahti, P. (Pekka), Mägi, R. (Reedik), Medland, S.E. (Sarah), Montgomery, G.W. (Grant), Nyholt, D.R. (Dale), Perola, M. (Markus), Pietilainen, K.H. (Kirsi Hannele), Salomaa, V. (Veikko), Sillanpää, E. (Elina), Suchiman, H.E. (H. Eka), Heemst, D. (Diana) van, Willemsen, G. (Gonneke), Agudo, A. (Antonio), Boeing, H. (Heiner), Boomsma, D.I. (Dorret), Chirlaque, M.D. (M.), Fagherazzi, G. (Guy), Ferrari, P. (Pietro), Franks, P. (Paul), Gieger, C. (Christian), Hagen, K. (Knut), Gunter, M.J. (Marc J.), Hägg, S. (Sara), Hovatta, I. (Iiris), Imaz, L. (Liher), Kaprio, J. (Jaakko), Kaaks, R. (Rudolf), Key, T. (Tim), Krogh, V. (Vittorio), Martin, N.G. (Nicholas), Melander, O. (Olle), Metspalu, A. (Andres), Moreno, C. (Concha), Onland-Moret, N.C. (N. Charlotte), Nilsson, P. (Peter), Ong, K.K. (Ken K.), Overvad, K. (Kim), Palli, D. (Domenico), Panico, S. (Salvatore), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Quirós, J.R., Jarvelin, M.R. (Marjo Riitta), Rodríguez-Barranco, M. (Miguel), Scott, R.A. (Robert A.), Severi, G. (Gianluca), Slagboom, P.E. (Eline), Spector, T.D. (Timothy), Tjønneland, A. (Anne), Trichopoulou, A. (Antonia), Tumino, R. (Rosario), Uitterlinden, A.G. (André G.), Schouw, Y.T. (Yvonne) van der, Duijn, C.M. (Cornelia) van, Weiderpass, E. (Elisabete), Denchi, E.L. (Eros Lazzerini), Matullo, G., Butterworth, A.S. (Adam S.), Danesh, J. (John), Samani, N.J. (Nilesh), Wareham, N.J. (Nick), Nelson, C.P. (Christopher P.), Langenberg, C. (Claudia), and Codd, V. (Veryan)

Abstract

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Published
2020
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5. Telomere Length and the Risk of Alzheimer's Disease: The Rotterdam Study

Author

Fani, L. (Lana), Hilal, S. (Saima), Sedaghat, S. (Sanaz), Broer, L. (Linda), Licher, S. (Silvan), Arp, P.P. (Pascal), van Meurs, J.B.J. (Joyce B J), Ikram, M.K. (Kamran), Ikram, M.A. (Arfan), Fani, L. (Lana), Hilal, S. (Saima), Sedaghat, S. (Sanaz), Broer, L. (Linda), Licher, S. (Silvan), Arp, P.P. (Pascal), van Meurs, J.B.J. (Joyce B J), Ikram, M.K. (Kamran), and Ikram, M.A. (Arfan)

Abstract

There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer's disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer's disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer's disease. We found a U-shaped associat

Published
2020
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6. Intestinal microbiome composition and its relation to joint pain and inflammation

Author

Boer, C.G. (Cindy), Radjabzadeh, D. (Djawad), Medina-Gomez, M.C. (Carolina), Garmaeva, S. (Sanzhima), Schiphof, D. (Dieuwke), Arp, P.P. (Pascal), Koet, T. (Thomas), Kurilshikov, A. (Alexander), Fu, J. (Jingyuan), Ikram, M.A. (Arfan), Bierma-Zeinstra, S.M. (Sita), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Zhernakova, A. (Alexandra), Meurs, J.B.J. (Joyce) van, Boer, C.G. (Cindy), Radjabzadeh, D. (Djawad), Medina-Gomez, M.C. (Carolina), Garmaeva, S. (Sanzhima), Schiphof, D. (Dieuwke), Arp, P.P. (Pascal), Koet, T. (Thomas), Kurilshikov, A. (Alexander), Fu, J. (Jingyuan), Ikram, M.A. (Arfan), Bierma-Zeinstra, S.M. (Sita), Uitterlinden, A.G. (André), Kraaij, R. (Robert), Zhernakova, A. (Alexandra), and Meurs, J.B.J. (Joyce) van

Abstract

Macrophage-mediated inflammation is thought to have a causal role in osteoarthritis-related pain and severity, and has been suggested to be triggered by endotoxins produced by the gastrointestinal microbiome. Here we investigate the relationship between joint pain and the gastrointestinal microbiome composition, and osteoarthritis-related knee pain in the Rotterdam Study; a large population based cohort study. We show that abundance of Streptococcus species is associated with increased knee pain, which we validate by absolute quantification of Streptococcus species. In addition, we replicate these results in 867 Caucasian adults of the Lifelines-DEEP study. Finally we show evidence that this association is driven by local inflammation in the knee joint. Our results indicate the microbiome is a possible therapeutic target for osteoarthritis-related knee pain.

Published
2019
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7. Vitamin D receptor polymorphisms are associated with reduced esophageal vitamin D receptor expression and reduced esophageal adenocarcinoma risk

Author

Janmaat, V.T. (Vincent), Winkel, A. (Anouk) van de, Peppelenbosch, M.P. (Maikel), Spaander, M.C.W. (Manon), Uitterlinden, A.G. (André), Pourfarzad, F. (Farzin), Tilanus, H.W. (Hugo), Rygiel, A.M. (Agnieszka), Moons, L.M.G. (Leon), Arp, P.P. (Pascal), Krishnadath, K.K. (Kausilia), Kuipers, E.J. (Ernst), Laan, L.J.W. (Luc) van der, Janmaat, V.T. (Vincent), Winkel, A. (Anouk) van de, Peppelenbosch, M.P. (Maikel), Spaander, M.C.W. (Manon), Uitterlinden, A.G. (André), Pourfarzad, F. (Farzin), Tilanus, H.W. (Hugo), Rygiel, A.M. (Agnieszka), Moons, L.M.G. (Leon), Arp, P.P. (Pascal), Krishnadath, K.K. (Kausilia), Kuipers, E.J. (Ernst), and Laan, L.J.W. (Luc) van der

Abstract

Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase–polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5’ regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention.

Published
2015
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8. Characteristics of de novo structural changes in the human genome

Author

Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Hormozdiari, F. (Fereydoun), Marschall, T. (Tanja), Hehir-Kwa, J. (Jayne), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Renkens, I. (Ivo), Van Roosmalen, M.J. (Markus J.), Arp, P.P. (Pascal), Coe, B.P. (Bradley P.), Handsaker, R.E. (Robert), Suchiman, E.D. (Eka D.), Cuppen, E. (Edwin), Thung, D.T. (Djie Tjwan), McVey, M. (Mitch), Wendl, M.C. (Michael C.), Uitterlinden, A.G. (André), Schönhuth, A. (Alexander), Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Ye, K. (Kai), Guryev, V. (Victor), Van Ommen, G.-J.B. (Gert-Jan B.), Kloosterman, W.P. (Wigard), Francioli, L.C. (Laurent), Hormozdiari, F. (Fereydoun), Marschall, T. (Tanja), Hehir-Kwa, J. (Jayne), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Renkens, I. (Ivo), Van Roosmalen, M.J. (Markus J.), Arp, P.P. (Pascal), Coe, B.P. (Bradley P.), Handsaker, R.E. (Robert), Suchiman, E.D. (Eka D.), Cuppen, E. (Edwin), Thung, D.T. (Djie Tjwan), McVey, M. (Mitch), Wendl, M.C. (Michael C.), Uitterlinden, A.G. (André), Schönhuth, A. (Alexander), Eichler, E.E. (Evan), Bakker, P.I.W. (Paul) de, Ye, K. (Kai), Guryev, V. (Victor), and Van Ommen, G.-J.B. (Gert-Jan B.)

Abstract

Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (120 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.

Published
2015
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9. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), Richards, J.B. (Brent), Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), and Richards, J.B. (Brent)

Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation

Published
2015
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10. The transcriptional landscape of age in human peripheral blood

Author

Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), Singleton, A., Peters, M.J. (Marjolein), Joehanes, R. (Roby), Pilling, L.C. (Luke), Schurmann, C. (Claudia), Conneely, K.N. (Karen N.), Powell, J.E. (Joseph), Reinmaa, E. (Eva), Sutphin, G.L. (George L.), Zhernakova, A. (Alexandra), Schramm, K. (Katharina), Wilson, Y.A. (Yana A.), Kobes, S. (Sayuko), Tukiainen, T. (Taru), Ramos, Y.F.M. (Yolande), Göring, H.H.H. (Harald H.), Fornage, M. (Myriam), Liu, Y. (YongMei), Gharib, S.A. (Sina), Stranger, B.E. (Barbara), Jager, P.L. (Philip) de, Aviv, A. (Abraham), Levy, D. (Daniel), Murabito, J. (Joanne), Munson, P.J. (Peter J.), Huan, T. (Tianxiao), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Rooij, J.G.J. (Jeroen) van, Stolk, L. (Lisette), Broer, L. (Linda), Verbiest, M.M.P.J. (Michael), Jhamai, M. (Mila), Arp, P.P. (Pascal), Metspalu, A. (Andres), Tserel, L. (Liina), Milani, L. (Lili), Samani, N.J. (Nilesh), Peterson, P. (Pärt), Kasela, S. (Silva), Codd, V. (Veryan), Peters, A. (Annette), Ward-Caviness, C.K. (Cavin K.), Herder, C. (Christian), Waldenberger, M. (Melanie), Roden, M. (Michael), Singmann, P. (Paula), Zeilinger, S. (Sonja), Illig, T. (Thomas), Homuth, G. (Georg), Grabe, H.J. (Hans Jörgen), Völzke, H. (Henry), Steil, L. (Leif), Kocher, T. (Thomas), Murray, A. (Anna), Melzer, D. (David), Yaghootkar, H. (Hanieh), Bandinelli, S., Moses, E.K. (Eric), Kent, J.W. (Jack), Curran, J.E. (Joanne), Johnson, M.P. (Matthew), Williams-Blangero, S. (Sarah), Westra, H.J. (Harm-Jan), McRae, A.F. (Allan F.), Smith, J.A. (Jennifer A), Kardia, S.L.R. (Sharon), Hovatta, I. (Iiris), Perola, M. (Markus), Ripatti, S. (Samuli), Salomaa, V. (Veikko), Henders, A.K. (Anjali), Martin, N.G. (Nicholas), Smith, A.K. (Alicia K.), Mehta, D. (Divya), Binder, E.B. (Elisabeth B.), Nylocks, K.M. (K. Maria), Kennedy, E.M. (Elizabeth M.), Klengel, T. (Torsten), Ding, J. (Jingzhong), Suchy-Dicey, A. (Astrid), Enquobahrie, D., Brody, J.A. (Jennifer A.), Rotter, J.I. (Jerome I.), Chen, Y.-D.I. (Yii-Der I.), Houwing-Duistermaat, J.J. (Jeanine), Kloppenburg, M. (Margreet), Slagboom, P.E. (Eline), Helmer, Q. (Quinta), Hollander, W. (Wouter) den, Bean, S. (Shannon), Raj, T. (Towfique), Bakhshi, N. (Noman), Wang, Q.P. (Qiao Ping), Oyston, L.J. (Lisa J.), Psaty, B.M. (Bruce), Tracy, R.P. (Russell), Montgomery, G.W. (Grant), Turner, S.T. (Stephen), Blangero, J. (John), Meulenbelt, I. (Ingrid), Ressler, K.J. (Kerry), Yang, J. (Jian), Franke, L. (Lude), Kettunen, J. (Johannes), Visscher, P.M. (Peter), Neely, G.G. (G. Gregory), Korstanje, R. (Ron), Hanson, R.L. (Robert L.), Prokisch, H. (Holger), Ferrucci, L. (Luigi), Esko, T. (Tõnu), Teumer, A. (Alexander), Meurs, J.B.J. (Joyce) van, Johnson, A.D. (Andrew D.), Nalls, M.A. (Michael), Hernandez, D.G. (Dena), Cookson, M.R. (Mark), Gibbs, R.J. (Raphael J.), Hardy, J. (John), Ramasamy, A. (Adaikalavan), Zonderman, A.B. (Alan B.), Dillman, A. (Allissa), Traynor, B. (Bryan), Smith, C. (Colin), Longo, D.L. (Dan L.), Trabzuni, D. (Danyah), Troncoso, J.C. (Juan), Brug, M.P. (Marcel) van der, Weale, M.E. (Michael), O'Brien, R. (Richard), Johnson, R. (Robert), Walker, R. (Robert), Zielke, R.H. (Ronald H.), Arepalli, S. (Sampath), Ryten, M. (Mina), and Singleton, A.

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015
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11. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

Author

Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), and Estrada Gil, K. (Karol)

Abstract

Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10−5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Published
2014
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12. Genetic association analysis of LARS2 with type 2 diabetes

Author

Reiling, E. (Erwin), Jafar-Mohammadi, B. (Bahram), Riet, E. (Esther) van 't, Weedon, M.N. (Michael), Vliet-Ostaptchouk, J.V. (Jana) van, Hansen, T. (Torben), Saxena, R. (Richa), Haeften, T.W. (Timon) van, Arp, P.P. (Pascal), S. Das, Nijpels, M.G.A.A.M. (Giel), Groenewoud, M.J. (Marlous), Hove, E.C. (Els) van, Uitterlinden, A.G. (André), Smit, J.W.A. (Jan), Morris, A.D. (Andrew), Doney, A.S.F. (Alex), Palmer, C.N.A. (Colin), Guiducci, C. (Candace), Hattersley, A.T. (Andrew), Frayling, T.M. (Timothy), Pedersen, O. (Oluf), Slagboom, P.E. (Eline), Altshuler, D. (David), Groop, L. (Leif), Romijn, J.A., Maassen, J.A. (Johannes), Hofker, M.A. (Marten), Dekker, J.M. (Jacqueline), McCarthy, M.I. (Mark), Hart, L.M. (Leen) 't, Reiling, E. (Erwin), Jafar-Mohammadi, B. (Bahram), Riet, E. (Esther) van 't, Weedon, M.N. (Michael), Vliet-Ostaptchouk, J.V. (Jana) van, Hansen, T. (Torben), Saxena, R. (Richa), Haeften, T.W. (Timon) van, Arp, P.P. (Pascal), S. Das, Nijpels, M.G.A.A.M. (Giel), Groenewoud, M.J. (Marlous), Hove, E.C. (Els) van, Uitterlinden, A.G. (André), Smit, J.W.A. (Jan), Morris, A.D. (Andrew), Doney, A.S.F. (Alex), Palmer, C.N.A. (Colin), Guiducci, C. (Candace), Hattersley, A.T. (Andrew), Frayling, T.M. (Timothy), Pedersen, O. (Oluf), Slagboom, P.E. (Eline), Altshuler, D. (David), Groop, L. (Leif), Romijn, J.A., Maassen, J.A. (Johannes), Hofker, M.A. (Marten), Dekker, J.M. (Jacqueline), McCarthy, M.I. (Mark), and Hart, L.M. (Leen) 't

Abstract

Aims/hypothesis: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF>5%) to type 2 diabetes risk. Methods: We combi

Published
2010
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13. A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22

Author

Kerkhof, J.M. (Hanneke), Lories, R.J. (Rik), Meulenbelt, I. (Ingrid), Jonsdottir, I. (Ingileif), Valdes, A.M. (Ana Maria), Arp, P.P. (Pascal), Ingvarsson, T. (Torvaldur), Jhamai, M. (Mila), Jonsson, H. (Helgi), Stolk, L. (Lisette), Thorleifsson, G. (Gudmar), Zhai, G. (Guangju), Zhang, F. (Feng), Zhu, Y. (Yicheng), Breggen, R. (Ruud) van der, Doherty, M. (Michael), Felson, D., Gonzalez, A. (Antonio), Halldorsson, B.V. (Bjarni), Hart, D.J. (Deborah), Hauksson, V.B. (Valdimar), Hofman, A. (Albert), Ioannidis, J.P.A. (John), Kloppenburg, M. (Margreet), Lane, N.E. (Nancy), Loughlin, J. (John), Luyten, F.P. (Frank), Nevitt, M.C. (Michael), Parimi, N. (Neeta), Pols, H.A.P. (Huib), Rivadeneira Ramirez, F. (Fernando), Slagboom, P.E. (Eline), Styrkarsdottir, U. (Unnur), Tsezou, A. (Aspasia), Putte, T. (Tom) van de, Zmuda, J. (Joseph), Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Carr, A.J. (Andrew Jonathan), Kerkhof, J.M. (Hanneke), Lories, R.J. (Rik), Meulenbelt, I. (Ingrid), Jonsdottir, I. (Ingileif), Valdes, A.M. (Ana Maria), Arp, P.P. (Pascal), Ingvarsson, T. (Torvaldur), Jhamai, M. (Mila), Jonsson, H. (Helgi), Stolk, L. (Lisette), Thorleifsson, G. (Gudmar), Zhai, G. (Guangju), Zhang, F. (Feng), Zhu, Y. (Yicheng), Breggen, R. (Ruud) van der, Doherty, M. (Michael), Felson, D., Gonzalez, A. (Antonio), Halldorsson, B.V. (Bjarni), Hart, D.J. (Deborah), Hauksson, V.B. (Valdimar), Hofman, A. (Albert), Ioannidis, J.P.A. (John), Kloppenburg, M. (Margreet), Lane, N.E. (Nancy), Loughlin, J. (John), Luyten, F.P. (Frank), Nevitt, M.C. (Michael), Parimi, N. (Neeta), Pols, H.A.P. (Huib), Rivadeneira Ramirez, F. (Fernando), Slagboom, P.E. (Eline), Styrkarsdottir, U. (Unnur), Tsezou, A. (Aspasia), Putte, T. (Tom) van de, Zmuda, J. (Joseph), Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, and Carr, A.J. (Andrew Jonathan)

Abstract

__Objective__ To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study. Methods. We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and ∼39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10-7considered genomewide significant. __Results__ The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10-8) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10-12). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. __Conclusion__ Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target.

Published
2010
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14. Vitamin D binding protein genotype and osteoporosis

Author

Fang, Y. (Yue), Meurs, J.B.J. (Joyce) van, Arp, P.P. (Pascal), Leeuwen, J.P.T.M. (Hans) van, Hofman, A. (Albert), Pols, H.A.P. (Huib), Uitterlinden, A.G. (André), Fang, Y. (Yue), Meurs, J.B.J. (Joyce) van, Arp, P.P. (Pascal), Leeuwen, J.P.T.M. (Hans) van, Hofman, A. (Albert), Pols, H.A.P. (Huib), and Uitterlinden, A.G. (André)

Abstract

Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D3for haplotype 1 (P = 3 × 10-4) and haplotype 2 (P = 3 × 10-6), respectively. Similar associations were observed for 1,25-(OH)2D3. The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06-2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and envir

Published
2009
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15. Vitamin D binding protein genotype and osteoporosis

Author

Fang, Y. (Yue), Meurs, J.B.J. (Joyce) van, Arp, P.P. (Pascal), Leeuwen, J.P.T.M. (Hans) van, Hofman, A. (Albert), Pols, H.A.P. (Huib), Uitterlinden, A.G. (André), Fang, Y. (Yue), Meurs, J.B.J. (Joyce) van, Arp, P.P. (Pascal), Leeuwen, J.P.T.M. (Hans) van, Hofman, A. (Albert), Pols, H.A.P. (Huib), and Uitterlinden, A.G. (André)

Abstract

Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D3for haplotype 1 (P = 3 × 10-4) and haplotype 2 (P = 3 × 10-6), respectively. Similar associations were observed for 1,25-(OH)2D3. The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06-2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and envir

Published
2009
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16. Growth hormone dose in growth hormone-deficient adults is not associated with IGF-1 gene polymorphisms

Author

Meyer, S. (Silke), Schaefer, S. (Stephan), Ivan, D. (Diana), Stolk, L. (Lisette), Arp, P.P. (Pascal), Uitterlinden, A.G. (André), Nawroth, P.P. (Peter), Plöckinger, U. (Ursula), Stalla, G.K. (Günter), Tuschy, U. (Ulrich), Weber, M.M. (Matthias), Weise, W.J. (Wolfgang), Pfützner, A. (Andreas), Kann, P. (Peter), Meyer, S. (Silke), Schaefer, S. (Stephan), Ivan, D. (Diana), Stolk, L. (Lisette), Arp, P.P. (Pascal), Uitterlinden, A.G. (André), Nawroth, P.P. (Peter), Plöckinger, U. (Ursula), Stalla, G.K. (Günter), Tuschy, U. (Ulrich), Weber, M.M. (Matthias), Weise, W.J. (Wolfgang), Pfützner, A. (Andreas), and Kann, P. (Peter)

Abstract

Aims: Several SNPs and a microsatellite cytosine-adenine repeat promoter polymorphisms of the IGF-1 gene have been reported to be associated with circulating IGF-1 serum concentrations. Variance in IGF-1 concentrations due to genetic variations may affect different response to growth hormone (GH) treatment, resulting in different individually required GH-doses in GH-defecient patients. The aim of this study was to test if the IGF-1 gene polymorphisms are associated with the GH-dose of GH-defecient adults. Materials & methods: A total of nine SNPs, five addtionally selected SNPs and a cytosine-adenine repeat polymorphism were determined in 133 German adult patients (66 men, 67 women; mean age 45.4 years ± 13.1 stamdard deviation; majority Caucasian) with GH-deficiency (GHD) of different origin, derived from the prospective Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. Patients received GH-treatment for 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH-dose after 1 year of treatment, IGF-1 concentrations, IGF-1-standard deviation score (SDS), the IGF-1:GH ratio and anthropometric data were analyzed by genotyped. Results: Except for rs1019731, which showed a significant difference of IGF-1-SDS by genotypes (p=0.02), all polymorphisms showed no associations with the GH-doses, IGF-1 concentrations, IGF-1-SDS and IGF-1:GH ration after adjusting for the confounding variable

Published
2009
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17. Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size

Author

Soranzo, N. (Nicole), Rivadeneira Ramirez, F. (Fernando), Chinappen-Horsley, U. (Usha), Malkina, I. (Ida), Richards, J.B. (Brent), Hammond, N. (Naomi), Stolk, L. (Lisette), Nica, A. (Alexandra), Inouye, M. (Michael), Hofman, A. (Albert), Stephens, J. (Jonathan), Wheeler, E. (Eleanor), Arp, P.P. (Pascal), Gwilliam, R. (Rhian), Jhamai, P.M. (Mila), Potter, S. (Simon), Chaney, A. (Amy), Ghori, M.J.R. (Mohammed), Ravindrarajah, R. (Radhi), Ermakov, S. (Sergey), Estrada Gil, K. (Karol), Pols, H.A.P. (Huib), Williams, F.M. (Frances), McArdle, W.L. (Wendy), Meurs, J.B.J. (Joyce) van, Loos, R.J.F. (Ruth), Frants, R.R. (Rune), Ahmadi, K.R. (Kourosh), Hart, D.J. (Deborah), Ouwehand, W.H. (Willem), Wareham, N.J. (Nick), Barroso, I.E. (Inês), Sandhu, M.S. (Manjinder), Strachan, D.P. (David), Demissie, S. (Serkalem), Livshits, G. (Gregory), Spector, T.D. (Timothy), Uitterlinden, A.G. (André), Soranzo, N. (Nicole), Rivadeneira Ramirez, F. (Fernando), Chinappen-Horsley, U. (Usha), Malkina, I. (Ida), Richards, J.B. (Brent), Hammond, N. (Naomi), Stolk, L. (Lisette), Nica, A. (Alexandra), Inouye, M. (Michael), Hofman, A. (Albert), Stephens, J. (Jonathan), Wheeler, E. (Eleanor), Arp, P.P. (Pascal), Gwilliam, R. (Rhian), Jhamai, P.M. (Mila), Potter, S. (Simon), Chaney, A. (Amy), Ghori, M.J.R. (Mohammed), Ravindrarajah, R. (Radhi), Ermakov, S. (Sergey), Estrada Gil, K. (Karol), Pols, H.A.P. (Huib), Williams, F.M. (Frances), McArdle, W.L. (Wendy), Meurs, J.B.J. (Joyce) van, Loos, R.J.F. (Ruth), Frants, R.R. (Rune), Ahmadi, K.R. (Kourosh), Hart, D.J. (Deborah), Ouwehand, W.H. (Willem), Wareham, N.J. (Nick), Barroso, I.E. (Inês), Sandhu, M.S. (Manjinder), Strachan, D.P. (David), Demissie, S. (Serkalem), Livshits, G. (Gregory), Spector, T.D. (Timothy), and Uitterlinden, A.G. (André)

Abstract

Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GWsignificant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10-8and rs910316 in TMED10, P-value = 1.4×10-7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10-7and rs849141 in JAZF1, P-value = 3.2×10-11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10-5and rs6817306 in LCORL, P-value = 4×10-4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10-4and rs4911494 at UQCC, P-value = 1.9×10-4), and femur length (including rs710841 at PRKG2, Pvalue = 2.4×10-5and rs10946808 at HIST1H1D, P-value = 6.4×10-6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

Published
2009
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18. Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene

Author

Kayser, M.H. (Manfred), Liu, F. (Fan), Janssens, A.C.J.W. (Cécile), Rivadeneira Ramirez, F. (Fernando), Lao Grueso, O. (Oscar), Duijn, K. (Kate) van, Vermeulen, M. (Mark), Arp, P.P. (Pascal), Jhamai, M. (Mila), IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Heath, S.C. (Simon), Zelenika, D. (Diana), Despriet, D.D.G. (Dominique), Klaver, C.C.W. (Caroline), Vingerling, J.R. (Hans), Jong, P.T.V.M. (Paulus) de, Hofman, A. (Albert), Aulchenko, Y.S. (Yurii), Uitterlinden, A.G. (André), Oostra, B.A. (Ben), Kayser, M.H. (Manfred), Liu, F. (Fan), Janssens, A.C.J.W. (Cécile), Rivadeneira Ramirez, F. (Fernando), Lao Grueso, O. (Oscar), Duijn, K. (Kate) van, Vermeulen, M. (Mark), Arp, P.P. (Pascal), Jhamai, M. (Mila), IJcken, W.F.J. (Wilfred) van, Dunnen, J.T. (Johan) den, Heath, S.C. (Simon), Zelenika, D. (Diana), Despriet, D.D.G. (Dominique), Klaver, C.C.W. (Caroline), Vingerling, J.R. (Hans), Jong, P.T.V.M. (Paulus) de, Hofman, A. (Albert), Aulchenko, Y.S. (Yurii), Uitterlinden, A.G. (André), and Oostra, B.A. (Ben)

Abstract

Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.

Published
2008
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19. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study

Author

Richards, J.B. (Brent), Rivadeneira Ramirez, F. (Fernando), Inouye, M. (Michael), Pastinen, T., Soranzo, N. (Nicole), Wilson, S.G. (Scott), Andrew, T. (Toby), Falchi, M. (Mario), Gwilliam, R. (Rhian), Ahmadi, K.R. (Kourosh), Valdes, A.M., Arp, P.P. (Pascal), Whittaker, P., Verlaan, D.J. (Dominique), Jhamai, M. (Mila), Kumanduri, V., Moorhouse, M.J. (Michael), Meurs, J.B.J. (Joyce) van, Hofman, A. (Albert), Pols, H.A.P. (Huib), Hart, D.J., Zhai, G. (Guangju), Kato, B.S., Mullin, B.H. (Benjamin), Zhang, F. (Feng), Deloukas, P. (Panagiotis), Uitterlinden, A.G. (André), Spector, T.D. (Timothy), Richards, J.B. (Brent), Rivadeneira Ramirez, F. (Fernando), Inouye, M. (Michael), Pastinen, T., Soranzo, N. (Nicole), Wilson, S.G. (Scott), Andrew, T. (Toby), Falchi, M. (Mario), Gwilliam, R. (Rhian), Ahmadi, K.R. (Kourosh), Valdes, A.M., Arp, P.P. (Pascal), Whittaker, P., Verlaan, D.J. (Dominique), Jhamai, M. (Mila), Kumanduri, V., Moorhouse, M.J. (Michael), Meurs, J.B.J. (Joyce) van, Hofman, A. (Albert), Pols, H.A.P. (Huib), Hart, D.J., Zhai, G. (Guangju), Kato, B.S., Mullin, B.H. (Benjamin), Zhang, F. (Feng), Deloukas, P. (Panagiotis), Uitterlinden, A.G. (André), and Spector, T.D. (Timothy)

Abstract

Background: Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density. Methods: In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. Findings: We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10-8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10-12for lumbar spine and p=1·9×10-4for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09-1·52, p=0·002) and osteoporosis (OR 1·3, 1·08-1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10-10for lumbar spine and p=3·3×10-8for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01-1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10-6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10-17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08-1·63, p=0·006) and this effect was independent of bone mineral density. Interpretation: Two gene variants of key bio

Published
2008
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20. Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene

Author

Hart, L.M. (Leen) 't, Pols, H.A.P. (Huib), Hansen, T. (Torben), Rietveld, I. (Ingrid), Dekker, J.M. (Jacqueline), Maassen, J.A. (Johannes), Nijpels, M.G.A.A.M. (Giel), Janssen, G.M.C. (George), Arp, P.P. (Pascal), Heine, R.J. (Robert), Uitterlinden, A.G. (André), Jorgensen, T. (Torben), Duijn, C.M. (Cornelia) van, Borch-Johnsen, K., Pedersen, O. (Oluf), Hart, L.M. (Leen) 't, Pols, H.A.P. (Huib), Hansen, T. (Torben), Rietveld, I. (Ingrid), Dekker, J.M. (Jacqueline), Maassen, J.A. (Johannes), Nijpels, M.G.A.A.M. (Giel), Janssen, G.M.C. (George), Arp, P.P. (Pascal), Heine, R.J. (Robert), Uitterlinden, A.G. (André), Jorgensen, T. (Torben), Duijn, C.M. (Cornelia) van, Borch-Johnsen, K., and Pedersen, O. (Oluf)

Abstract

Previously, we have shown that a mutation in the mitochondrial DNA-encoded tRNA(Leu(UUR)) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNA(Leu(UUR)). In this study, we have examined whether variants in the leucyl tRNA synthetase gene (LARS2), involved in aminoacylation of tRNA(Leu(UUR)), associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations in the Netherlands and Denmark. A -109 g/a variant was not associated with type 2 diabetes. Allele frequencies for the other variant, H324Q, were 3.5% in type 2 diabetic and 2.7% in control subjects, respectively. The common odds ratio across all four studies was 1.40 (95% CI 1.12-1.76), P = 0.004. There were no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established. This is the first report of association between an aminoacyl tRNA synthetase gene and disease. Our results further highlight the important role of mitochondria in glucose homeostasis.

Published
2005

21. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites

Author

Uitterlinden, A.G. (André), Arp, P.P. (Pascal), Paeper, B.W., Charmley, P., Proll, S. (Sean), Rivadeneira Ramirez, F. (Fernando), Fang, Y. (Yue), Meurs, J.B.J. (Joyce) van, Britschgi, T.B., Latham, J.A., Schatzman, R.C., Pols, H.A.P. (Huib), Brunkow, M.E., Uitterlinden, A.G. (André), Arp, P.P. (Pascal), Paeper, B.W., Charmley, P., Proll, S. (Sean), Rivadeneira Ramirez, F. (Fernando), Fang, Y. (Yue), Meurs, J.B.J. (Joyce) van, Britschgi, T.B., Latham, J.A., Schatzman, R.C., Pols, H.A.P. (Huib), and Brunkow, M.E.

Abstract

Osteoporosis has a strong genetic component, but the genes involved are poorly defined. We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD). Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease. We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and wo

Published
2004
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22. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites

Author

Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Britschgi, T.B., Brunkow, M.E., Latham, J.A., Pols, H.A.P. (Huib), Schatzman, R.C., Arp, P.P. (Pascal), Paeper, B.W., Charmley, P., Proll, S., Rivadeneira Ramirez, F. (Fernando), Fang, Y. (Yue), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Britschgi, T.B., Brunkow, M.E., Latham, J.A., Pols, H.A.P. (Huib), Schatzman, R.C., Arp, P.P. (Pascal), Paeper, B.W., Charmley, P., Proll, S., Rivadeneira Ramirez, F. (Fernando), and Fang, Y. (Yue)

Abstract

Osteoporosis has a strong genetic component, but the genes involved are poorly defined. We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD). Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease. We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites. A 3-bp insertion (f=0.38) in the presumed SOST promoter region (SRP3) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006). Similarly, a G variant (f=0.40) in the van Buchem deletion region (SRP9) was associated with increased BMD in men at the FN (P=.007) and LS (P=.02). In both cases, differences between extreme genotypes reached 0.2 SD. We observed no genotype effects on fracture risk, for the 234 osteoporotic fractures validated during 8.2 years of follow-up and for the 146 vertebral prevalent fractures analyzed. We did not find association between any of several frequent haplotypes across the SOST gene region and BMD. We did find evidence of additive effects of SRP3 with the COLIA1 Sp1 polymorphism but not with haplotypes of 3' polymorphisms in the vitamin-D receptor gene. The SOST-COLIA1 additive effect increased with age and reached 0.5 SD difference in BMD at LS in the oldest age group (P=.02). The molecular mechanism whereby these moderate SOST genotype effects are mediated remains to be elucidated, but it is likely to involve differences in regulation of SOST gene expression.

Published
2004

23. Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk

Author

Colin, E.M. (Edgar), Uitterlinden, A.G. (André), Bergink, A.P. (Arjan), Klift, M. (Marjolein) van der, Fang, Y. (Yue), Arp, P.P. (Pascal), Pols, H.A.P. (Huib), Leeuwen, J.P.T.M. (Hans) van, Meurs, J.B.J. (Joyce) van, Hofman, A. (Albert), Colin, E.M. (Edgar), Uitterlinden, A.G. (André), Bergink, A.P. (Arjan), Klift, M. (Marjolein) van der, Fang, Y. (Yue), Arp, P.P. (Pascal), Pols, H.A.P. (Huib), Leeuwen, J.P.T.M. (Hans) van, Meurs, J.B.J. (Joyce) van, and Hofman, A. (Albert)

Abstract

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERalpha haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERalpha haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERalpha and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density.

Published
2003
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24. Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk

Author

Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Pols, H.A.P. (Huib), Weel, A.E.A.M. (Angelique), Klift, M. (Marjolein) van der, Bergink, A.P. (Arjan), Arp, P.P. (Pascal), Fang, Y. (Yue), Duijn, C.M. (Cornelia) van, Leeuwen, J.P.T.M. (Hans) van, Klein Nagelvoort-Schuit, S.C.E. (Stephanie), Hofman, A. (Albert), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Pols, H.A.P. (Huib), Weel, A.E.A.M. (Angelique), Klift, M. (Marjolein) van der, Bergink, A.P. (Arjan), Arp, P.P. (Pascal), Fang, Y. (Yue), Duijn, C.M. (Cornelia) van, Leeuwen, J.P.T.M. (Hans) van, Klein Nagelvoort-Schuit, S.C.E. (Stephanie), and Hofman, A. (Albert)

Abstract

This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects. We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof. We observed only three of the possible four PvuII-XbaI haplotypes in our population. A comparison with other Caucasian populations showed similar haplotype frequencies, while in Asian and African populations these were different. Linkage disequilibrium (LD) analysis between the PvuII-XbaI haplotype and the (TA)(n) repeat showed strong LD between the two sites. Reconstruction of long range haplotypes over the entire 5' region, revealed six frequent LRH. In men, we did not observe an association between the ESR1 polymorphisms studied a

Published
2003
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