The East Flanders Prospective Twin Survey (Belgium): a population–based register
In: Twin research, Band 1, Heft 4, S. 167-175
ISSN: 2053-6003
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In: Twin research, Band 1, Heft 4, S. 167-175
ISSN: 2053-6003
In: Twin research, Band 4, Heft 5, S. 356-364
ISSN: 2053-6003
AbstractAn adverse intra-uterine environment has been associated with abdominal fat distribution in singletons. Twins often have a low birth weight and a short gestation. Therefore, they may have an increased risk to develop abdominal obesity. Furthermore, monozygotic monochorionic twins (MZ MC) have a larger intra-pair birth weight difference compared to monozygotic dichorionic twins (MZ DC). If adult anthropometry is programmed in utero, this may affect the intra-pair correlations in adulthood and, consequently, also the results from the classic twin method to estimate genetic and environmental influences. In the present study, we compared the absolute values, the intra-pair differences, and the intra-pair correlations of body mass, height, BMI, and abdominal fat distribution of 424 MZ MC, MZ DC and dizygotic (DZ) twin pairs (aged 18–34 yrs). DZ, MZ DC and MZ MC twins did not differ for most anthropometric characteristics. Only MZ women tended (p = 0.03) to accumulate more abdominal fat compared to DZ twins. Overall, the contribution of zygosity and chorion type to adult anthropometry was rather low (≤ 1.7%). Although the intra-pair birth weight difference of MZ MC pairs (10.5% in men, 12.3% in women) was significantly larger compared to that of MZ DC pairs (6.9% and 9.2% resp.), the intra-pair differences in adult anthropometry were similar for both MZ twin types. Also the intra-pair correlations of MZ MC and MZ DC pairs were strikingly alike, suggesting no significant influence of the prenatal environment on adult concordance. In conclusion, the substantial difference in the prenatal environment of MZ MC and MZ DC twins did not result in a difference in intra-pair concordance of adult anthropometry and fat distribution. Therefore, we suggest that the chorion type of MZ twins does not bias the twin design and the estimation of the genetic contribution to adult anthropometry.
In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 10, Heft S1, S. 6-7
ISSN: 1839-2628
AbstractUnlike-sex twins provide a unique natural experiment to investigate the influence of sex on gestation. Our data showed that length of gestation of unlike-sex pairs is similar to that of female same-sex pairs, and significantly (0.4 wks,p= .02) longer than that of male same-sex pairs. Birthweight of female unlike-sex twins was similar to female same-sex twins, but male unlike-sex twins weighed 78 g more than male same-sex twins (p= .001). These data show that in unlikesex pairs it is the girl that prolongs gestation for her brother, resulting in a higher birthweight than that of same-sex boys.
In: Twin research, Band 6, Heft 1, S. 19-21
ISSN: 2053-6003
In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 9, Heft 5, S. 664-672
ISSN: 1839-2628
AbstractThe purpose of this study is to present curves of estimated placental growth in twins and to evaluate the relative contribution of gestational age, zygosity, chorionicity, fusion of the placentas, sex of the individual and of the twin pair, site of the umbilical cord insertion, birth order, maternal age, and parity. Perinatal data and placental data were obtained from 6315 live-born twin pairs from the East Flanders Prospective Twin Survey. Of 4318 twin pairs, with no missing values, the placental weights of different gestational ages were analyzed using a nonlinear multivariate Gaussian regression. Two groups were distinguished: (1) twins with two separate placentas, and (2) twins with only one placental mass (one placenta in case of monochorionic twins or two fused placentas in case of dichorionic placentas). Overall, placental weight was influenced by gestational age, fusion of the placentas, and parity. In the case of one placental mass, monozygotic dichorionic twins had the lowest weights. If two separate placentas were present, birth order played a role in favor of the first-born twin. For parity and zygosity, the differences were most pronounced between 27 and 29 weeks, whereas the difference for birth order was most pronounced between 33 and 37 weeks. In conclusion, basic physiological characteristics, routinely examined at birth, influence placental weight. Taking these covariates into account allows a better evaluation of the placental weight given a gestational age, as an indicator of growth.
In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 10, Heft S1, S. 15-18
ISSN: 1839-2628
AbstractAlongitudinal study of growth and physical fitness of twins and their parents was designed in 1985. The major aims of this Leuven Longitudinal Twin Study were to quantify the genetic and environmental determination of (1) somatic characteristics, biological maturation and physical performance characteristics during the growth process, (2) the growth and developmental patterns, and (3) the covariation in somatic and performance characteristics.
In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 11, Heft 2, S. 224-235
ISSN: 1839-2628
AbstractThe assessment of fetal growth is an essential component of good antenatal care, especially for twins. The aims of this study are to develop twin-specific intrauterine 'growth' charts, based on cross-sectional birthweight data, for monochorionic and dichorionic twins according to sex and parity, and to detect twins at risk for neonatal death by comparing the use of twin-specific and singleton charts. The study sample consisted of 76,471 singletons and 8454 twins (4227 pairs) born in East Flanders (Belgium). Birthweights were analyzed using a nonlinear Gaussian regression. After 33 weeks of gestation, the birthweights of twins started to deviate from singletons (difference of 900 grams at 42 weeks). Birthweights of dichorionic twins continued to increase, whereas those of monochorionic twins decreased after week 40 (difference of more than 300 g at 42 weeks). After 31 weeks of gestation, neonatal mortality increased as centile decreased, and was especially high if birthweight was below the twin-specific third centile: .032 (below) versus .007 (above). Using singleton centiles, this was less obvious. In conclusion, twin-specific growth charts, taking chorionicity into account, are more accurate to detect twins at risk for neonatal death. Therefore the presented charts, based on cross-sectional birthweight data, enable an improved assessment of twin growth.
In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 11, Heft 5, S. 505-516
ISSN: 1839-2628
AbstractInsulin resistance and obesity are underlying causes of type 2 diabetes and therefore much interest is focused on the potential genes involved. A series of anthropometric and metabolic characteristic were measured in 240 MZ and 112 DZ twin pairs recruited from the East Flanders Prospective Twin Survey. Microsatellite markers located close to ABCC8, ADIPOQ, GCK, IGF1, IGFBP1, INSR, LEP, LEPR, PPARγ and the RETN gene were genotyped. Univariate single point variance components linkage analyses were performed using two methods: (1) the standard method, only comprising the phenotypic and genotypic data of the DZ twin pairs and (2) the extended method, also incorporating the phenotypic data of the MZ twin pairs. Suggestive linkages (LOD > 1) were observed between the ABCC8 marker and waist-to-hip ratio and HDL-cholesterol levels. Both markers flanking ADIPOQ showed suggestive linkage with triglycerides levels, the upstream marker also with body mass and HDL-cholesterol levels. The IGFBP1 marker showed suggestive linkage with fat mass, fasting insulin and leptin levels and the LEP marker showed suggestive linkage with birth weight. This study suggests that DNA variants in ABCC8, ADIPOQ, IGFBP1 and LEP gene region may predispose to type 2 diabetes. In addition, the two methods used to perform linkage analyses yielded similar results. This was however not the case for birth weight where chorionicity seems to be an important confounder.
In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 20, Heft 5, S. 395-405
ISSN: 1839-2628
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. ; To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. ; Academy of Finland 77299 102318 110413 118065 123885 124243 129680 129293 129494 136895 139635 141005 213506 251217 Agence Nationale de la Recherche (France) American Diabetes Association 7-08-MN-OK Association Francaise des Diabetiques Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques (France) Association Diabete Risque Vasculaire (France) British Diabetic Association (BDA) Research (UK) British Heart Foundation RG/98002 RG2008/08 Cancer Research UK Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) (USA) Chief Scientist Office, Scotland CZB/4/672 City of Kuopio (Finland) City of Leutkirch (Germany) Department of Health (UK) Deutsche Forschungsgemeinschaft ER1 55/6-2 Diabetes UK Doris Duke Charitable Foundation (USA) Estonian government SF0180142s0 European Commission: ENGAGE HEALTH-F4-2007-201413 EXGENESIS LSHM-CT-2004-005272 245536 QLG1-CT-2002-00896 2004310 European Commission (Marie Curie: FP7-PEOPLE-IEF) European Regional Development Fund Faculty of Medicine at the Norwegian University of Science and Technology Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish ...
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CONTEXT: Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. OBJECTIVE: The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. DESIGN: Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). PATIENTS OR OTHER PARTICIPANTS: In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. MAIN OUTCOME MEASURES: Blood concentrations of 25(OH)D were measured for all participants. RESULTS: Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. CONCLUSIONS: Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.
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Publisher's version (útgefin grein) ; Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D. ; WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The grant funding of WHI are R21 HL123677, R56 DK104806 and R01 MD012765 to NF. The FamHS was funded by R01HL118305 and R01HL117078 NHLBI grants, and 5R01DK07568102 and 5R01DK089256 NIDDK grant." and "The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (project # Z01-AG000513 and human subjects protocol number 09-AGN248). Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL119443, HL087660, HL054464, HL054457, and HL054481) of the National Institutes of Health. Ruth loos is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). The Rotterdam Study GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006- 01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002- 01254). The ERF study was further supported by ENGAGE consortium and CMSB. Highthroughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWORFBR 047.017.043).ERF was further supported by the ZonMw grant (project 91111025), and this work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). This study is also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Drs. Meigs, Dupuis and Florez, NIDDK K24 DK080140 to Dr. Meigs, and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez. The HERITAGE Family Study was supported by National Heart, Lung, and Blood Institute grant HL-45670. The Women's Genome Health Study is supported by the National Heart, Lung, and Blood Instutute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913). Additional support for endpoint collection was provided by the National Heart, Lung, and Blood Institute under ARRA funding (HL099355). HyperGEN (Hypertension Genetic Epidemiology Network): The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673- 12. The AGES study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease)"and "Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6, the Scottish Funding Council HR03006 and the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z) for Stratifying Resilience and Depression Longitudinally (STRADL). Genotyping was funded by the UK's Medical Research Council. Jose C. Florez, NIDDK K24 DK110550 The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Additionally, one or more authors are affiliated with the following commercial entities: Interleukin Genetics, GlaxoSmithKline, Daiichi-Sankyo, AstraZeneca, Data Tecnica International LLC, Illumina Inc., University of California Healthcare, Janssen Pharmaceuticals, Goldfinch Bio, and Novo Nordisk. Please see the Competing Interests Statement for additional details. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. ; Peer Reviewed
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Data Availability: Our study data are now available at the following URL on the AMP T2D Knowledge Portal: http://www.kp4cd.org/dataset_downloads/t2d. Funding: WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The grant funding of WHI are R21 HL123677, R56 DK104806 and R01 MD012765 to NF. The FamHS was funded by R01HL118305 and R01HL117078 NHLBI grants, and 5R01DK07568102 and 5R01DK089256 NIDDK grant." and "The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (project # Z01-AG000513 and human subjects protocol number 09-AGN248). Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL119443, HL087660, HL054464, HL054457, and HL054481) of the National Institutes of Health. Ruth loos is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). The Rotterdam Study GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006- 01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002- 01254). The ERF study was further supported by ENGAGE consortium and CMSB. Highthroughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWORFBR 047.017.043).ERF was further supported by the ZonMw grant (project 91111025), and this work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6- 4278). This study is also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Drs. Meigs, Dupuis and Florez, NIDDK K24 DK080140 to Dr. Meigs, and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez. The HERITAGE Family Study was supported by National Heart, Lung, and Blood Institute grant HL-45670. The Women's Genome Health Study is supported by the National Heart, Lung, and Blood Instutute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913). Additional support for endpoint collection was provided by the National Heart, Lung, and Blood Institute under ARRA funding (HL099355). HyperGEN (Hypertension Genetic Epidemiology Network): The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515, and 2 R01 HL55673- 12. The AGES study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease)"and "Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6, the Scottish Funding Council HR03006 and the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z) for Stratifying Resilience and Depression Longitudinally (STRADL). Genotyping was funded by the UK's Medical Research Council. Jose C. Florez, NIDDK K24 DK110550 The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Additionally, one or more authors are affiliated with the following commercial entities: Interleukin Genetics, GlaxoSmithKline, Daiichi-Sankyo, AstraZeneca, Data Tecnica International LLC, Illumina Inc., University of California Healthcare, Janssen Pharmaceuticals, Goldfinch Bio, and Novo Nordisk. Please see the Competing Interests Statement for additional details. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. ; Peer reviewed ; Publisher PDF
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Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
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HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples. ; 3C. Three-City Study. The work was made possible by the participation of the control subjects, the patients, and their families. We thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The 3C Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM "Cohortes et collections de données biologiques" programme. Lille Génopôle received an unconditional grant from Eisai. AGES. Age, Gene/Environment Susceptibility-Reykjavik Study. This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC. Atherosclerosis Risk in Communities study. The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This work as well as YL and AK were supported by the German Research Foundation (KO 3598/2-1, KO 3598/3-1 and CRC1140 A05 to AK). ASPS. Austrian Stroke Prevention Study. The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. The authors thank the staff and the participants of the ASPS for their valuable contributions. We thank Birgit Reinhart for her long-term administrative commitment and Ing Johann Semmler for the technical assistance at creating the DNA-bank. BMES. Blue Mountains Eye Study. The BMES has been supported by the Australian RADGAC grant (1992- 94) and Australian National Health & Medical Research Council, Canberra Australia (Grant Nos: 974159, 211069, 991407, 457349). The GWAS studies of Blue Mountains Eye Study population are supported by the Australian National Health & Medical Research Council (Grant Nos: 512423, 475604, 529912) and the Wellcome Trust, UK (2008). EGH and JJW are funded by the Australian National Health & Medical Research Council Fellowship Schemes. CILENTO. Italian Network on Genetic Isolates – Cilento. We thank the populations of Cilento for their participation in the study. The study was supported by the Italian Ministry of Universities and CNR 36 (PON03PE_00060_7, Interomics Flagship Project), the Assessorato Ricerca Regione Campania, the Fondazione con il SUD (2011-PDR-13), and the Istituto Banco di Napoli - Fondazione to MC. COLAUS. The CoLaus authors thank Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey and Sylvie Mermoud for data collection. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (33CSCO- 122661, 3200BO-111361/2, 3100AO-116323/1, 310000-112552). The computations for CoLaus imputation were performed in part at the Vital-IT center for high performance computing of the Swiss Institute of Bioinformatics. We thank Vincent Mooser for his contribution to the CoLaus study. EGCUT. Estonian Genome Center University of Tartu. EGCUT received financing from FP7 grants (278913, 306031, 313010) and targeted financing from Estonian Government (SF0180142s08). EGCUT studies were covered from Infra-structure grant no. 3.2.0304.11-0312 funded mostly by the European Regional Development Fund, Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG). We acknowledge EGCUT technical personnel, especially Mr V. Soo and S. Smit. Data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. FamHS. Family Heart Study. The FHS work was supported in part by NIH grants 5R01HL08770003, 5R01HL08821502 (Michael A. Province) from the NHLBI and 5R01DK07568102, 5R01DK06833603 from the NIDDK (I.B.B.). The authors thank the staff and participants of the FamHS for their important contributions. FHS. Framingham Heart Study. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. GENDIAN. GENetics of DIAbetic Nephropathy study. The support of the physicians, the patients, and the staff of the Diabetes Zentrum Mergentheim (Head: Prof. Dr. Thomas Haak), the diabetes outpatient clinic Dr Nusser - Dr Kreisel, the dialysis centers KfH Amberg, KfH Bayreuth, KfH Deggendorf, KfH Donauwörth, KfH Freising, KfH Freyung, KfH Fürth, KfH Hof, KfH Ingolstadt, KfH Kelheim, KfH München Elsenheimerstraße, KfH München-Schwabing, KfH Neumarkt, KfH Neusäß, KfH Oberschleißheim, KfH Passau, KfH Plauen, KfH Regensburg Günzstraße, KfH Regensburg Caritas-Krankenhaus, KfH Straubing, KfH Sulzbach-Rosenberg, KfH Weiden, Dialysezentrum Augsburg Dr. Kirschner, Dialysezentrum Bad Alexandersbad, KfH Bamberg, Dialysezentrum Emmering, Dialysezentrum Klinikum Landshut, Dialysezentrum Landshut, Dialysezentrum Pfarrkirchen, Dialysezentrum Schwandorf, Dr. Angela Götz, the medical doctoral student Johanna Christ and the Study Nurse Ingrid Lugauer. The expert technical assistance of Claudia Strohmeier is acknowledged. Phenotyping was funded by the Dr. Robert PflegerStiftung (Dr Carsten A. Böger), the MSD Stipend Diabetes (Dr Carsten A. Böger) and the University Hospital of Regensburg (intramural grant ReForM A to Dr. A. Götz, ReForM C to Dr. Carsten Böger). Genome-wide genotyping was funded by the KfH Stiftung Präventivmedizin e.V. (Dr. Carsten A. Böger, Dr. Jens Brüning), the Else Kröner-Fresenius-Stiftung (2012_A147 to Dr Carsten A. Böger and Dr Iris M. Heid) and the University Hospital Regensburg (Dr Carsten A. Böger). Data analysis was funded by the Else 37 Kröner-Fresenius Stiftung (Dr. Iris M. Heid and Dr. Carsten A. Böger: 2012_A147; Dr. Carsten A. Böger and Dr. Bernhard K. Krämer: P48/08//A11/08). GENDIAN Study Group: Mathias Gorski, Iris M. Heid, Bernhard K. Krämer, Myriam Rheinberger, Michael Broll, Alexander Lammert, Jens Brüning, Matthias Olden, Klaus Stark, Claudia Strohmeier, Simone Neumeier, Sarah Hufnagel, Petra Jackermeier, Emilia Ruff, Johanna Christ, Peter Nürnberg, Thomas Haak, Carsten A. Böger. HABC. Health Aging and Body Composition Study. The HABC study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HCS. Hunter Community Study. The University of Newcastle provided $300,000 from its Strategic Initiatives Fund, and $600,000 from the Gladys M Brawn Senior Research Fellowship scheme; Vincent Fairfax Family Foundation, a private philanthropic trust, provided $195,000; The Hunter Medical Research Institute provided media support during the initial recruitment of participants; and Dr Anne Crotty, Prof. Rodney Scott and Associate Prof. Levi provided financial support towards freezing costs for the long-term storage of participant blood samples. The authors would like to thank the men and women participating in the HCS as well as all the staff, investigators and collaborators who have supported or been involved in the project to date. A special thank you should go to Alison Koschel and Debbie Quain who were instrumental in setting up the pilot study and initial phase of the project. HPFS. Health Professionals Follow-Up Study. The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental & Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). We thank the staff and participants of the NHS and HPFS for their dedication and commitment. INGI-CARLANTINO. Italian Network on Genetic Isolates – Carlantino. We thank Anna Morgan and Angela D'Eustacchio for technical support. We are grateful to the municipal administrators for their collaboration on the project and for logistic support. We thank all participants to this study. INGI-FVG. Italian Network on Genetic Isolates – Friuli Venezia-Giulia. We thank Anna Morgan and Angela D'Eustacchio for technical support. We are grateful to the municipal administrators for their collaboration on the project and for logistic support. We thank all participants to this study. 38 INGI-VAL BORBERA. Italian Network on Genetic Isolates – Val Borbera. We thank the inhabitants of the Val Borbera who made this study possible, the local administrations and the ASL-Novi Ligure (Al) for support. We also thank Clara Camaschella for data collection supervision and organization of the clinical data collection, Fiammetta Vigano` for technical help and Corrado Masciullo for building the analysis platform. The research was supported by funds from Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy and Ministry of Health, Ricerca Finalizzata 2008 and 2011/2012, CCM 2010, PRIN 2009 and Telethon, Italy to DT. IPM. Mount Sinai BioMe Biobank Program. The Mount Sinai BioMe Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. KORA-F3 and F4. The genetic epidemiological work was funded by the NIH subcontract from the Children's Hospital, Boston, US, (H.E.W., I.M.H, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (H.E.W. 01GS0823; WK project A3, number 01GS0834), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else KrönerFresenius-Stiftung (P48/08//A11/08; C.A.B., B.K.K; 2012_A147 to CAB and IMH.). The Genetic Epidemiology at the University of Regensburg received financial contributions from the BMBF (01ER1206 and 01ER1507). The kidney parameter measurements in F3 were funded by the Else Kröner-FreseniusStiftung (C.A.B., B.K.K.) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (W.K.). Genome wide genotyping costs in F3 and F4 were in part funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). De novo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum München. The LINUX platform for computation were funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center. LIFELINES. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. Lifelines group authors: Behrooz Z Alizadeh1 , H Marike Boezen1 , Lude Franke2 , Pim van der Harst3 , Gerjan Navis4 , Marianne Rots5 , Harold Snieder1 , Morris Swertz2 , Bruce HR Wolffenbuttel6 and Cisca Wijmenga2 1. Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands 2. Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands 3. Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands 4. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands 5. Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands 6. Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands MESA. Multi-Ethnic Study of Atherosclerosis. University of Washington (N01-HC-95159),Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University 39 (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC- 95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL- 071205) MICROS. Microisolates in South Tyrol study. We owe a debt of gratitude to all participants. We thank the primary care practitioners R. Stocker, S. Waldner, T. Pizzecco, J. Plangger, U. Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). NESDA. The Netherlands Study of Depression and Anxiety. The infrastructure for the NESDA study is funded through the Geestkracht programme of the Dutch Scientific Organization (ZON-MW, grant number 10-000-1002) and matching funds from participating universities and mental health care organizations. Genotyping in NESDA was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health. NHS. Nurses' Health Study. The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental & Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C). The NHS renal function and albuminuria work was supported by DK66574. Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). We thank the staff and participants of the NHS and HPFS for their dedication and commitment. NSPHS. The Northern Swedish Population Health Study. The NSPHS was supported by grants from the Swedish Natural Sciences Research Council, the European Union through the EUROSPAN project (contract no. LSHG-CT-2006-018947), the Foundation for Strategic Research (SSF) and the Linneaus Centre for Bioinformatics (LCB). We are also grateful for the contribution of samples from the Medical Biobank in Umeå and for the contribution of the district nurse Svea Hennix in the Karesuando study. RS-I. The Rotterdam Study. The GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Dr Michael 40 Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the GWAS database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners and the pharmacists. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G, for access to their grid resources. Abbas Dehghan is supported by NWO grant (vici, 918-76-619). SAPALDIA. Swiss Study on Air Pollution and Lung Diseases in Adults. The SAPALDIA Team: Study directorate: T Rochat (p), NM Probst Hensch (e/g), N Künzli (e/exp), C Schindler (s), JM Gaspoz (c) Scientific team: JC Barthélémy (c), W Berger (g), R Bettschart (p), A Bircher (a), O Brändli (p), C Brombach (n), M Brutsche (p), L Burdet (p), M Frey (p), U Frey (pd), MW Gerbase (p), D Gold (e/c/p), E de Groot (c), W Karrer (p), R Keller (p), B Martin (pa), D Miedinger (o), U Neu (exp), L Nicod (p), M Pons (p), F Roche (c), T Rothe (p), E Russi (p), P Schmid-Grendelmeyer (a), A Schmidt-Trucksäss (pa), A Turk (p), J Schwartz (e), D. Stolz (p), P Straehl (exp), JM Tschopp (p), A von Eckardstein (cc), E Zemp Stutz (e). Scientific team at coordinating centers: M Adam (e/g), C Autenrieth (pa), PO Bridevaux (p), D Carballo (c), E Corradi (exp), I Curjuric (e), J Dratva (e), A Di Pasquale (s), E Dupuis Lozeron (s), E Fischer (e), M Germond (s), L Grize (s), D Keidel (s), S Kriemler (pa), A Kumar (g), M Imboden (g), N Maire (s), A Mehta (e), H Phuleria (exp), E Schaffner (s), GA Thun (g) A Ineichen (exp), M Ragettli (e), M Ritter (exp), T Schikowski (e), M Tarantino (s), M Tsai (exp) (a) allergology, (c) cardiology, (cc) clinical chemistry, (e) epidemiology, (exp) exposure, (g) genetic and molecular biology, (m) meteorology, (n) nutrition, (o) occupational health, (p) pneumology, (pa) physical activity, (pd) pediatrics, (s) statistics. Funding: The Swiss National Science Foundation (grants no 33CSCO-134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO- 104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099), the Federal Office for Forest, Environment and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton's Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais and Zurich, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA. The study could not have been done without the help of the study participants, technical and administrative support and the medical teams and field workers at the local study sites. Local fieldworkers : Aarau: S Brun, G Giger, M Sperisen, M Stahel, Basel: C Bürli, C Dahler, N Oertli, I Harreh, F Karrer, G Novicic, N Wyttenbacher, Davos: A Saner, P Senn, R Winzeler, Geneva: F Bonfils, B Blicharz, C Landolt, J Rochat, Lugano: S Boccia, E Gehrig, MT Mandia, G Solari, B Viscardi, Montana: AP Bieri, C Darioly, M Maire, Payerne: F Ding, P Danieli A Vonnez, Wald: D Bodmer, E Hochstrasser, R Kunz, C Meier, J Rakic, U Schafroth, A Walder. Administrative staff: C Gabriel, R Gutknecht. SHIP and SHIP-TREND. The Study of Health in Pomerania. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 41 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. The SHIP authors are grateful to Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation as well as to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum München) for the genotyping of the SHIP-TREND cohort. TRAILS. TRacking Adolescents' Individual Lives. Trails is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60- 60600-98-018 and 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 457-03-018, GB-MaGW 452-04-314, and GB-MaGW 452-06- 004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013); the Sophia Foundation for Medical Research (projects 301 and 393), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), and the participating universities. We are grateful to all adolescents, their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. WGHS. Women's Genome Health Study. The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen. YFS. Young Finns Study. The YFS has been financially supported by the Academy of Finland: grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 and 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (T.L). The technical assistance in the statistical analyses by Ville Aalto and Irina Lisinen is acknowledged. ; Peer Reviewed
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