Author: "Kemp, John P." / Topic: genetic predisposition to disease - Searchworks@Jio Institute Digital Library Search Results

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21 results on '"Kemp, John P."'

1. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Author: Steinthorsdottir V, McGinnis R, Williams NO, Stefansdottir L, Thorleifsson G, Shooter S, Fadista J, Sigurdsson JK, Auro KM, Berezina G, Borges MC, Bumpstead S, Bybjerg-Grauholm J, Colgiu I, Dolby VA, Dudbridge F, Engel SM, Franklin CS, Frigge ML, Frisbaek Y, Geirsson RT, Geller F, Gretarsdottir S, Gudbjartsson DF, Harmon Q, Hougaard DM, Hegay T, Helgadottir A, Hjartardottir S, Jääskeläinen T, Johannsdottir H, Jonsdottir I, Juliusdottir T, Kalsheker N, Kasimov A, Kemp JP, Kivinen K, Klungsøyr K, Lee WK, Melbye M, Miedzybrodska Z, Moffett A, Najmutdinova D, Nishanova F, Olafsdottir T, Perola M, Pipkin FB, Poston L, Prescott G, Saevarsdottir S, Salimbayeva D, Scaife PJ, Skotte L, Staines-Urias E, Stefansson OA, Sørensen KM, Thomsen LCV, Tragante V, Trogstad L, Simpson NAB, Aripova T, Casas JP, Dominiczak AF, Walker JJ, Thorsteinsdottir U, Iversen AC, Feenstra B, Lawlor DA, Boyd HA, Magnus P, Laivuori H, Zakhidova N, Svyatova G, Stefansson K, and Morgan L
Subjects: Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Asia, Central epidemiology, Blood Pressure genetics, Case-Control Studies, Datasets as Topic, Europe epidemiology, Female, Fibroblast Growth Factor 5 genetics, Genetic Loci genetics, Genome-Wide Association Study, Humans, Hypertension, Pregnancy-Induced epidemiology, MDS1 and EVI1 Complex Locus Protein genetics, Middle Aged, Pre-Eclampsia epidemiology, Pregnancy, Prospective Studies, Genetic Predisposition to Disease, Hypertension, Pregnancy-Induced genetics, Multifactorial Inheritance, Pre-Eclampsia genetics
Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
Published: 2020
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2. An atlas of genetic influences on osteoporosis in humans and mice.

Author: Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, Vulpescu NA, Forgetta V, Kleinman A, Mohanty ST, Sergio CM, Quinn J, Nguyen-Yamamoto L, Luco AL, Vijay J, Simon MM, Pramatarova A, Medina-Gomez C, Trajanoska K, Ghirardello EJ, Butterfield NC, Curry KF, Leitch VD, Sparkes PC, Adoum AT, Mannan NS, Komla-Ebri DSK, Pollard AS, Dewhurst HF, Hassall TAD, Beltejar MG, Adams DJ, Vaillancourt SM, Kaptoge S, Baldock P, Cooper C, Reeve J, Ntzani EE, Evangelou E, Ohlsson C, Karasik D, Rivadeneira F, Kiel DP, Tobias JH, Gregson CL, Harvey NC, Grundberg E, Goltzman D, Adams DJ, Lelliott CJ, Hinds DA, Ackert-Bicknell CL, Hsu YH, Maurano MT, Croucher PI, Williams GR, Bassett JHD, Evans DM, and Richards JB
Subjects: Adult, Aged, Animals, Female, Fractures, Bone genetics, Genome-Wide Association Study methods, Humans, Male, Mice, Mice, Knockout, Middle Aged, Phenotype, Polymorphism, Single Nucleotide genetics, Bone Density genetics, Genetic Predisposition to Disease genetics, Osteoporosis genetics
Abstract: Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10 -75 ) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
Published: 2019
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3. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Author: McGinnis R, Steinthorsdottir V, Williams NO, Thorleifsson G, Shooter S, Hjartardottir S, Bumpstead S, Stefansdottir L, Hildyard L, Sigurdsson JK, Kemp JP, Silva GB, Thomsen LCV, Jääskeläinen T, Kajantie E, Chappell S, Kalsheker N, Moffett A, Hiby S, Lee WK, Padmanabhan S, Simpson NAB, Dolby VA, Staines-Urias E, Engel SM, Haugan A, Trogstad L, Svyatova G, Zakhidova N, Najmutdinova D, Dominiczak AF, Gjessing HK, Casas JP, Dudbridge F, Walker JJ, Pipkin FB, Thorsteinsdottir U, Geirsson RT, Lawlor DA, Iversen AC, Magnus P, Laivuori H, Stefansson K, and Morgan L
Subjects: Cohort Studies, Female, Follow-Up Studies, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Pregnancy, Pregnancy Proteins genetics, Vascular Endothelial Growth Factor Receptor-1 blood, Fetus, Genetic Predisposition to Disease, Pre-Eclampsia genetics, Vascular Endothelial Growth Factor Receptor-1 genetics
Abstract: Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10 -11 ) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.
Published: 2017
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4. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

Author: Fan Q, Verhoeven VJ, Wojciechowski R, Barathi VA, Hysi PG, Guggenheim JA, Höhn R, Vitart V, Khawaja AP, Yamashiro K, Hosseini SM, Lehtimäki T, Lu Y, Haller T, Xie J, Delcourt C, Pirastu M, Wedenoja J, Gharahkhani P, Venturini C, Miyake M, Hewitt AW, Guo X, Mazur J, Huffman JE, Williams KM, Polasek O, Campbell H, Rudan I, Vatavuk Z, Wilson JF, Joshi PK, McMahon G, St Pourcain B, Evans DM, Simpson CL, Schwantes-An TH, Igo RP, Mirshahi A, Cougnard-Gregoire A, Bellenguez C, Blettner M, Raitakari O, Kähönen M, Seppala I, Zeller T, Meitinger T, Ried JS, Gieger C, Portas L, van Leeuwen EM, Amin N, Uitterlinden AG, Rivadeneira F, Hofman A, Vingerling JR, Wang YX, Wang X, Tai-Hui Boh E, Ikram MK, Sabanayagam C, Gupta P, Tan V, Zhou L, Ho CE, Lim W, Beuerman RW, Siantar R, Tai ES, Vithana E, Mihailov E, Khor CC, Hayward C, Luben RN, Foster PJ, Klein BE, Klein R, Wong HS, Mitchell P, Metspalu A, Aung T, Young TL, He M, Pärssinen O, van Duijn CM, Jin Wang J, Williams C, Jonas JB, Teo YY, Mackey DA, Oexle K, Yoshimura N, Paterson AD, Pfeiffer N, Wong TY, Baird PN, Stambolian D, Wilson JE, Cheng CY, Hammond CJ, Klaver CC, Saw SM, Rahi JS, Korobelnik JF, Kemp JP, Timpson NJ, Smith GD, Craig JE, Burdon KP, Fogarty RD, Iyengar SK, Chew E, Janmahasatian S, Martin NG, MacGregor S, Xu L, Schache M, Nangia V, Panda-Jonas S, Wright AF, Fondran JR, Lass JH, Feng S, Zhao JH, Khaw KT, Wareham NJ, Rantanen T, Kaprio J, Pang CP, Chen LJ, Tam PO, Jhanji V, Young AL, Döring A, Raffel LJ, Cotch MF, Li X, Yip SP, Yap MK, Biino G, Vaccargiu S, Fossarello M, Fleck B, Yazar S, Tideman JW, Tedja M, Deangelis MM, Morrison M, Farrer L, Zhou X, Chen W, Mizuki N, Meguro A, and Mäkelä KM
Subjects: Asian People genetics, Gene Expression Profiling, Humans, Polymorphism, Single Nucleotide genetics, White People genetics, Educational Status, Environment, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Refractive Errors genetics
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Published: 2016
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5. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Author: Paternoster L, Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, Curtin JA, Bønnelykke K, Tian C, Takahashi A, Esparza-Gordillo J, Alves AC, Thyssen JP, den Dekker HT, Ferreira MA, Altmaier E, Sleiman PM, Xiao FL, Gonzalez JR, Marenholz I, Kalb B, Yanes MP, Xu CJ, Carstensen L, Groen-Blokhuis MM, Venturini C, Pennell CE, Barton SJ, Levin AM, Curjuric I, Bustamante M, Kreiner-Møller E, Lockett GA, Bacelis J, Bunyavanich S, Myers RA, Matanovic A, Kumar A, Tung JY, Hirota T, Kubo M, McArdle WL, Henderson AJ, Kemp JP, Zheng J, Smith GD, Rüschendorf F, Bauerfeind A, Lee-Kirsch MA, Arnold A, Homuth G, Schmidt CO, Mangold E, Cichon S, Keil T, Rodríguez E, Peters A, Franke A, Lieb W, Novak N, Fölster-Holst R, Horikoshi M, Pekkanen J, Sebert S, Husemoen LL, Grarup N, de Jongste JC, Rivadeneira F, Hofman A, Jaddoe VW, Pasmans SG, Elbert NJ, Uitterlinden AG, Marks GB, Thompson PJ, Matheson MC, Robertson CF, Ried JS, Li J, Zuo XB, Zheng XD, Yin XY, Sun LD, McAleer MA, O'Regan GM, Fahy CM, Campbell LE, Macek M, Kurek M, Hu D, Eng C, Postma DS, Feenstra B, Geller F, Hottenga JJ, Middeldorp CM, Hysi P, Bataille V, Spector T, Tiesler CM, Thiering E, Pahukasahasram B, Yang JJ, Imboden M, Huntsman S, Vilor-Tejedor N, Relton CL, Myhre R, Nystad W, Custovic A, Weiss ST, Meyers DA, Söderhäll C, Melén E, Ober C, Raby BA, Simpson A, Jacobsson B, Holloway JW, Bisgaard H, Sunyer J, Hensch NMP, Williams LK, Godfrey KM, Wang CA, Boomsma DI, Melbye M, Koppelman GH, Jarvis D, McLean WI, Irvine AD, Zhang XJ, Hakonarson H, Gieger C, Burchard EG, Martin NG, Duijts L, Linneberg A, Jarvelin MR, Noethen MM, Lau S, Hübner N, Lee YA, Tamari M, Hinds DA, Glass D, Brown SJ, Heinrich J, Evans DM, and Weidinger S
Subjects: Case-Control Studies, Dermatitis, Atopic pathology, Humans, Immunity, Innate genetics, Risk Factors, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Dermatitis, Atopic ethnology, Dermatitis, Atopic genetics, Ethnicity genetics, Genetic Loci, Genetic Markers genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
Abstract: Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.
Published: 2015
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6. Genetic variation in prostate-specific antigen-detected prostate cancer and the effect of control selection on genetic association studies.

Author: Knipe DW, Evans DM, Kemp JP, Eeles R, Easton DF, Kote-Jarai Z, Al Olama AA, Benlloch S, Donovan JL, Hamdy FC, Neal DE, Smith GD, Lathrop M, and Martin RM
Subjects: Aged, Genetic Association Studies, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Genetic Predisposition to Disease genetics, Prostate-Specific Antigen genetics, Prostatic Neoplasms genetics
Abstract: Background: Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls., Methods: We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA < 0.5 ng/mL) or "high" (PSA ≥ 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA., Results: The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates < 0.04). We found a novel inverse association of rs9311171-T with circulating PSA., Conclusions: Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA., Impact: These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria., (©2014 American Association for Cancer Research.)
Published: 2014
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7. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

Author: Cheng CY, Schache M, Ikram MK, Young TL, Guggenheim JA, Vitart V, MacGregor S, Verhoeven VJ, Barathi VA, Liao J, Hysi PG, Bailey-Wilson JE, St Pourcain B, Kemp JP, McMahon G, Timpson NJ, Evans DM, Montgomery GW, Mishra A, Wang YX, Wang JJ, Rochtchina E, Polasek O, Wright AF, Amin N, van Leeuwen EM, Wilson JF, Pennell CE, van Duijn CM, de Jong PT, Vingerling JR, Zhou X, Chen P, Li R, Tay WT, Zheng Y, Chew M, Burdon KP, Craig JE, Iyengar SK, Igo RP Jr, Lass JH Jr, Chew EY, Haller T, Mihailov E, Metspalu A, Wedenoja J, Simpson CL, Wojciechowski R, Höhn R, Mirshahi A, Zeller T, Pfeiffer N, Lackner KJ, Bettecken T, Meitinger T, Oexle K, Pirastu M, Portas L, Nag A, Williams KM, Yonova-Doing E, Klein R, Klein BE, Hosseini SM, Paterson AD, Makela KM, Lehtimaki T, Kahonen M, Raitakari O, Yoshimura N, Matsuda F, Chen LJ, Pang CP, Yip SP, Yap MK, Meguro A, Mizuki N, Inoko H, Foster PJ, Zhao JH, Vithana E, Tai ES, Fan Q, Xu L, Campbell H, Fleck B, Rudan I, Aung T, Hofman A, Uitterlinden AG, Bencic G, Khor CC, Forward H, Pärssinen O, Mitchell P, Rivadeneira F, Hewitt AW, Williams C, Oostra BA, Teo YY, Hammond CJ, Stambolian D, Mackey DA, Klaver CC, Wong TY, Saw SM, and Baird PN
Subjects: Adolescent, Adult, Aged, Asian People, Axial Length, Eye pathology, Eye Proteins metabolism, Female, Gene Expression, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Refractive Errors ethnology, Refractive Errors pathology, Signal Transduction, White People, Axial Length, Eye metabolism, Eye Proteins genetics, Genetic Loci, Genetic Predisposition to Disease, Refractive Errors genetics
Abstract: Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2013
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8. Whole‐genome sequencing identifies EN1 as a determinant of bone density and fracture

Author: Zheng, Hou‐Feng, Forgetta, Vincenzo, Hsu, Yi‐Hsiang, Estrada, Karol, Rosello‐Diez, Alberto, Leo, Paul J, Dahia, Chitra L, Park‐Min, Kyung Hyun, Tobias, Jonathan H, Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching‐Ti, Uggla, Charlotta, Evans, Daniel S, Nielson, Carrie M, Walter, Klaudia, Pettersson‐Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen‐Chi, Mokry, Lauren E, Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia‐Ho, Cheung, Warren, Medina‐Gómez, Carolina, Ge, Bing, Chen, Shu‐Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A, Gregson, Celia L, Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J, Marshall, Mhairi, Gardiner, Brooke B, Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y, Thorleifsson, Gudmar, Enneman, Anke W, van Schoor, Natasja M, de Groot, Lisette CPGM, van der Velde, Nathalie, Melin, Beatrice, Kemp, John P, Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G, Williams, Stephen R, Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z, Haessler, Jeff, Chasman, Daniel I, Giulianini, Franco, Rose, Lynda M, Ridker, Paul M, Eisman, John A, Nguyen, Tuan V, Center, Jacqueline R, Nogues, Xavier, Garcia‐Giralt, Natalia, Launer, Lenore L, Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M, Karlsson, Magnus K, Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, and Arp, Pascal P
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Human Genome, Biotechnology, Osteoporosis, Stem Cell Research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, Musculoskeletal, Injuries and accidents, Animals, Bone Density, Bone and Bones, Disease Models, Animal, Europe, Exome, Female, Fractures, Bone, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genomics, Genotype, Homeodomain Proteins, Humans, Mice, Sequence Analysis, DNA, White People, Wnt Proteins, AOGC Consortium, UK10K Consortium, General Science & Technology
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 ncontrols = 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 reference panels to study the genetic architecture of complex traits and disease in the general population.
Published: 2015

9. Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

Author: de Moor, Marleen HM, van den Berg, Stéphanie M, Verweij, Karin JH, Krueger, Robert F, Luciano, Michelle, Vasquez, Alejandro Arias, Matteson, Lindsay K, Derringer, Jaime, Esko, Tõnu, Amin, Najaf, Gordon, Scott D, Hansell, Narelle K, Hart, Amy B, Seppälä, Ilkka, Huffman, Jennifer E, Konte, Bettina, Lahti, Jari, Lee, Minyoung, Miller, Mike, Nutile, Teresa, Tanaka, Toshiko, Teumer, Alexander, Viktorin, Alexander, Wedenoja, Juho, Abecasis, Goncalo R, Adkins, Daniel E, Agrawal, Arpana, Allik, Jüri, Appel, Katja, Bigdeli, Timothy B, Busonero, Fabio, Campbell, Harry, Costa, Paul T, Smith, George Davey, Davies, Gail, de Wit, Harriet, Ding, Jun, Engelhardt, Barbara E, Eriksson, Johan G, Fedko, Iryna O, Ferrucci, Luigi, Franke, Barbara, Giegling, Ina, Grucza, Richard, Hartmann, Annette M, Heath, Andrew C, Heinonen, Kati, Henders, Anjali K, Homuth, Georg, Hottenga, Jouke-Jan, Iacono, William G, Janzing, Joost, Jokela, Markus, Karlsson, Robert, Kemp, John P, Kirkpatrick, Matthew G, Latvala, Antti, Lehtimäki, Terho, Liewald, David C, Madden, Pamela AF, Magri, Chiara, Magnusson, Patrik KE, Marten, Jonathan, Maschio, Andrea, Medland, Sarah E, Mihailov, Evelin, Milaneschi, Yuri, Montgomery, Grant W, Nauck, Matthias, Ouwens, Klaasjan G, Palotie, Aarno, Pettersson, Erik, Polasek, Ozren, Qian, Yong, Pulkki-Råback, Laura, Raitakari, Olli T, Realo, Anu, Rose, Richard J, Ruggiero, Daniela, Schmidt, Carsten O, Slutske, Wendy S, Sorice, Rossella, Starr, John M, St Pourcain, Beate, Sutin, Angelina R, Timpson, Nicholas J, Trochet, Holly, Vermeulen, Sita, Vuoksimaa, Eero, Widen, Elisabeth, Wouda, Jasper, Wright, Margaret J, Zgaga, Lina, Porteous, David, Minelli, Alessandra, Palmer, Abraham A, Rujescu, Dan, Ciullo, Marina, Hayward, Caroline, and Rudan, Igor
Subjects: Biological Sciences, Genetics, Biological Psychology, Epidemiology, Social and Personality Psychology, Health Sciences, Psychology, Mental Health, Brain Disorders, Major Depressive Disorder, Serious Mental Illness, Human Genome, Mental Illness, Depression, 2.1 Biological and endogenous factors, Mental health, Adaptor Proteins, Signal Transducing, Anxiety Disorders, Cell Adhesion Molecules, Cell Adhesion Molecules, Neuronal, Depressive Disorder, Major, Genetic Predisposition to Disease, Genome-Wide Association Study, Guanylate Kinases, Humans, Multifactorial Inheritance, Neuroticism, Personality, Polymorphism, Single Nucleotide, Risk Factors, Genetics of Personality Consortium, Other Medical and Health Sciences, Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract: ImportanceNeuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases).ObjectivesTo identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD.Design, setting, and participantsGenome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014.Main outcomes and measuresNeuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.ResultsA genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12
Published: 2015

10. Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder.

Author: Genetics of Personality Consortium, de Moor, Marleen HM, van den Berg, Stéphanie M, Verweij, Karin JH, Krueger, Robert F, Luciano, Michelle, Arias Vasquez, Alejandro, Matteson, Lindsay K, Derringer, Jaime, Esko, Tõnu, Amin, Najaf, Gordon, Scott D, Hansell, Narelle K, Hart, Amy B, Seppälä, Ilkka, Huffman, Jennifer E, Konte, Bettina, Lahti, Jari, Lee, Minyoung, Miller, Mike, Nutile, Teresa, Tanaka, Toshiko, Teumer, Alexander, Viktorin, Alexander, Wedenoja, Juho, Abecasis, Goncalo R, Adkins, Daniel E, Agrawal, Arpana, Allik, Jüri, Appel, Katja, Bigdeli, Timothy B, Busonero, Fabio, Campbell, Harry, Costa, Paul T, Davey Smith, George, Davies, Gail, de Wit, Harriet, Ding, Jun, Engelhardt, Barbara E, Eriksson, Johan G, Fedko, Iryna O, Ferrucci, Luigi, Franke, Barbara, Giegling, Ina, Grucza, Richard, Hartmann, Annette M, Heath, Andrew C, Heinonen, Kati, Henders, Anjali K, Homuth, Georg, Hottenga, Jouke-Jan, Iacono, William G, Janzing, Joost, Jokela, Markus, Karlsson, Robert, Kemp, John P, Kirkpatrick, Matthew G, Latvala, Antti, Lehtimäki, Terho, Liewald, David C, Madden, Pamela AF, Magri, Chiara, Magnusson, Patrik KE, Marten, Jonathan, Maschio, Andrea, Medland, Sarah E, Mihailov, Evelin, Milaneschi, Yuri, Montgomery, Grant W, Nauck, Matthias, Ouwens, Klaasjan G, Palotie, Aarno, Pettersson, Erik, Polasek, Ozren, Qian, Yong, Pulkki-Råback, Laura, Raitakari, Olli T, Realo, Anu, Rose, Richard J, Ruggiero, Daniela, Schmidt, Carsten O, Slutske, Wendy S, Sorice, Rossella, Starr, John M, St Pourcain, Beate, Sutin, Angelina R, Timpson, Nicholas J, Trochet, Holly, Vermeulen, Sita, Vuoksimaa, Eero, Widen, Elisabeth, Wouda, Jasper, Wright, Margaret J, Zgaga, Lina, Porteous, David, Minelli, Alessandra, Palmer, Abraham A, Rujescu, Dan, Ciullo, Marina, and Hayward, Caroline
Subjects: Genetics of Personality Consortium, Humans, Genetic Predisposition to Disease, Cell Adhesion Molecules, Neuronal, Risk Factors, Personality, Anxiety Disorders, Depressive Disorder, Major, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Neuroticism, Adaptor Proteins, Signal Transducing, Cell Adhesion Molecules, Guanylate Kinases, Neuronal, Depressive Disorder, Major, Polymorphism, Single Nucleotide, Adaptor Proteins, Signal Transducing, Other Medical and Health Sciences, Psychology, Cognitive Sciences
Abstract: ImportanceNeuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases).ObjectivesTo identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD.Design, setting, and participantsGenome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014.Main outcomes and measuresNeuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.ResultsA genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12
Published: 2015

11. A genome-wide association meta-analysis identifies new childhood obesity loci

Author: Bradfield, Jonathan P, Taal, H Rob, Timpson, Nicholas J, Scherag, Andre, Lecoeur, Cecile, Warrington, Nicole M, Hypponen, Elina, Holst, Claus, Valcarcel, Beatriz, Thiering, Elisabeth, Salem, Rany M, Schumacher, Fredrick R, Cousminer, Diana L, Sleiman, Patrick MA, Zhao, Jianhua, Berkowitz, Robert I, Vimaleswaran, Karani S, Jarick, Ivonne, Pennell, Craig E, Evans, David M, St Pourcain, Beate, Berry, Diane J, Mook-Kanamori, Dennis O, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G, van Duijn, Cornelia M, van der Valk, Ralf JP, de Jongste, Johan C, Postma, Dirkje S, Boomsma, Dorret I, Gauderman, W James, Hassanein, Mohamed T, Lindgren, Cecilia M, Magi, Reedik, Boreham, Colin AG, Neville, Charlotte E, Moreno, Luis A, Elliott, Paul, Pouta, Anneli, Hartikainen, Anna-Liisa, Li, Mingyao, Raitakari, Olli, Lehtimaki, Terho, Eriksson, Johan G, Palotie, Aarno, Dallongeville, Jean, Das, Shikta, Deloukas, Panos, McMahon, George, Ring, Susan M, Kemp, John P, Buxton, Jessica L, Blakemore, Alexandra IF, Bustamante, Mariona, Guxens, Monica, Hirschhorn, Joel N, Gillman, Matthew W, Kreiner-Moller, Eskil, Bisgaard, Hans, Gilliland, Frank D, Heinrich, Joachim, Wheeler, Eleanor, Barroso, Ines, O'Rahilly, Stephen, Meirhaeghe, Aline, Sorensen, Thorkild IA, Power, Chris, Palmer, Lyle J, Hinney, Anke, Widen, Elisabeth, Farooqi, I Sadaf, McCarthy, Mark I, Froguel, Philippe, Meyre, David, Hebebrand, Johannes, Jarvelin, Marjo-Riitta, Jaddoe, Vincent WV, Smith, George Davey, Hakonarson, Hakon, and Grant, Struan FA
Subjects: Biological Sciences, Genetics, Pediatric, Nutrition, Obesity, Human Genome, Metabolic and endocrine, Oral and gastrointestinal, Stroke, Cancer, Cardiovascular, Adolescent, Adult, Body Mass Index, Case-Control Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Young Adult, Early Growth Genetics Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (
Published: 2012

12. An atlas of genetic influences on osteoporosis in humans and mice

Author: Morris, John A, Kemp, John P, Youlten, Scott E, Laurent, Laetitia, Logan, John G, Chai, Ryan C, Vulpescu, Nicholas A, Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu T, Sergio, C Marcelo, Quinn, Julian, Nguyen-Yamamoto, Loan, Luco, Aimee-Lee, Vijay, Jinchu, Simon, Marie-Michelle, Pramatarova, Albena, Medina-Gomez, Carolina, Trajanoska, Katerina, Ghirardello, Elena J, Butterfield, Natalie C, Curry, Katharine F, Leitch, Victoria D, Sparkes, Penny C, Adoum, Anne-Tounsia, Mannan, Naila S, Komla-Ebri, Davide SK, Pollard, Andrea S, Dewhurst, Hannah F, Hassall, Thomas AD, Beltejar, Michael-John G, 23andMe Research Team, Adams, Douglas J, Vaillancourt, Suzanne M, Kaptoge, Stephen, Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia E, Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P, Tobias, Jonathan H, Gregson, Celia L, Harvey, Nicholas C, Grundberg, Elin, Goltzman, David, Adams, David J, Lelliott, Christopher J, Hinds, David A, Ackert-Bicknell, Cheryl L, Hsu, Yi-Hsiang, Maurano, Matthew T, Croucher, Peter I, Williams, Graham R, Bassett, JH Duncan, Evans, David M, Richards, J Brent, Morris, John A [0000-0003-2769-8202], Kemp, John P [0000-0002-9105-2249], Youlten, Scott E [0000-0001-9314-2945], Vulpescu, Nicholas A [0000-0003-1310-0257], Sergio, C Marcelo [0000-0002-5426-0583], Medina-Gomez, Carolina [0000-0001-7999-5538], Reeve, Jonathan [0000-0002-4364-2682], Ntzani, Evangelia E [0000-0003-3712-4181], Rivadeneira, Fernando [0000-0001-9435-9441], Kiel, Douglas P [0000-0001-8474-0310], Gregson, Celia L [0000-0001-6414-0529], Harvey, Nicholas C [0000-0002-8194-2512], Lelliott, Christopher J [0000-0001-8087-4530], Hinds, David A [0000-0002-4911-803X], Williams, Graham R [0000-0002-8555-8219], Bassett, JH Duncan [0000-0003-0817-0082], Evans, David M [0000-0003-0663-4621], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Mice, Knockout, Middle Aged, Polymorphism, Single Nucleotide, Fractures, Bone, Mice, Phenotype, Bone Density, Animals, Humans, Osteoporosis, Female, Genetic Predisposition to Disease, Aged, Genome-Wide Association Study
Abstract: Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
Published: 2019

13. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, Pediatrics, Epidemiology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Public and occupational health, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, ACS - Atherosclerosis & ischemic syndromes, APH - Global Health, Epidemiology and Data Science, Medical Research Council (MRC), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, Clinicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Faculty of Medicine, Timo Strandberg / Principal Investigator, Department of Medicine, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, Developmental Psychology Research Group, Genetic Epidemiology, Genomic Discoveries and Clinical Translation, Cognitive and Brain Aging, Middeldorp, Christel M [0000-0002-6218-0428], and Apollo - University of Cambridge Repository
Subjects: Male, Netherlands Twin Register (NTR), embarazo, Epidemiology, C840 Clinical Psychology, LD SCORE REGRESSION, humanos, LOCI, Medizin, adolescente, Genome-wide association study, BLOOD-PRESSURE, Disease, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Pregnancy, Medicine, 030212 general & internal medicine, Early childhood, C820 Developmental Psychology, estudios de cohortes, Child, C440 Molecular Genetics, Public, Environmental & Occupational Health, Genetics, education.field_of_study, United Kingdom/epidemiology, COMMON VARIANTS, Hälsovetenskaper, adulto, A900 Others in Medicine and Dentistry, 3142 Public health care science, environmental and occupational health, 3. Good health, predicción, ddc, Childhood traits and disorders, Phenotype, Disease/genetics, Research Design, Child, Preschool, fenotipo, Female, ICEP, medicine.symptom, CHILDHOOD OBESITY, Life Sciences & Biomedicine, EArly Genetics Lifecourse Epidemiology (EAGLE) consortium, Adult, medicine.medical_specialty, Adolescent, Birth weight, Population, Consortium, Childhood Traits And Disorders, Longitudinal, enfermedad, Childhood obesity, 1117 Public Health and Health Services, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Health Sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, LONGITUDINAL TWIN, METAANALYSIS, lactante, Science & Technology, Early Growth Genetics (EGG) consortium, business.industry, Infant, Newborn, Infant, predisposición genética a la enfermedad, medicine.disease, BODY-MASS, C800 Psychology, BIRTH-WEIGHT, C420 Human Genetics, United Kingdom, Low birth weight, business, diseño de la investigación, Forecasting
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites., We are grateful to all families and participants who took part in these studies. We also acknowledge and appreciate the unique efforts of the research teams and practitioners contributing to the collection of this wealth of data. C. M. M. is supported by funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 721567. J. F. F. has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). R. M. F. and R. N. B. are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). D. L. C. is funded by the American Diabetes Association Grant 1-17-PDF-077. D. O. M-K. was supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). N. M. W. is supported by an Australian National Health and Medical Research Council Early Career Fellowship (APP1104818). T. S. A. was partially funded by the Gene-Diet Interactions in Obesity (GENDINOB) project on behalf of GOYA male cohort data management and analyses and acknowledges the same. S. D. was supported by National Institute of Health Research. T. M. F. is supported by the European Research Council grant: 323195 SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).H.H.is funded by The Children's Hospital of Philadelphia Endowed Chair in Genomic Research. A. T. H. is supported by the Wellcome Trust Senior Investigator Awards (WT098395), National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219). J. Hebebrand received grants from German Research Society, German Ministry of Education and Research. M-F. H. is currently supported by an American Diabetes Association (ADA) Pathway Program Accelerator Early Investigator Award (1-15-ACE-26). S. J. is supported by Helse Vest no. 23929, Bergen Forskningsstiftelse and KG Jebsen Foundation and University of Bergen. J. K. has been supported by the Academy of Finland Research Professor program (grants 265240 & 263278). J. P. K. is funded by a University of Queensland Development Fellowship (UQFEL1718945). H. L. has served as a speaker for Eli-Lilly and Shire and has received research grants from Shire; all outside the submitted work. C. M. L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). S. E. M. was funded by an NHMRC Senior Reseach Fellowship (APP1103623). K. Panoutsopoulou is funded by a career development fellowship (grant 20308) and by the Wellcome Trust (WT098051). C. P. at UCL Institute of Child Health, with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. I. P. was funded in part by the Wellcome Trust (WT205915), and the European Union's Horizon 2020 research, the European Union FP7-IDEAS-ERC Advanced Grant (GEPIDIAB, ERC-AG -ERC-294785), and innovation programme (DYNAhealth, H2020-PHC-2014-633595). R. C. R. is supported by CRUK (grant number C18281/A19169). J. G. S. is supported by an NHMRC Practitioner Fellowship Grant (APP1105807). J. T.; r is funded by the European Regional Development Fund (ERDF), the European Social Fund (ESF), Convergence Programme for Cornwall and the Isles of Scilly and the Diabetes Research and Wellness Foundation Non-Clinical Fellowship. N. V-T. is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B 00636), Generalitat de Catalunya. T. G. M. V was supported by ZonMW (TOP 40-00812-98-11010. J. F. W. is supported by the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease. H. Y. is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NL (CP2013-50). E. Z. is supported by the Wellcome Trust (098051). B. F. is supported by Novo Nordisk Foundation (12955) and an Oak Foundation Fellowship. S. S. and M-R. J. have received funding from the European Union's Horizon 2020 research and innovation programme [under grant agreement No 633595] for the DynaHEALTH action. P. R. N. was supported by the European Research Council (ERC), University of Bergen, KG Jebsen and Helse Vest. G. D. S. works within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1). D. A. L was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (Grant number 669545; DevelopObese), US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MC_UU_00011/6), Wellcome Trust GWAS grant (WT088806), an NIHR Senior Investigator Award (NF-SI-0611-10196) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L. Paternoster was supported by the UK Medical Research Council Unit grants MC_UU_12013_5. N. J. T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 102215/2/13/2), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361), a European Research Council Consolidator Grant (ERC-2014-CoG-648916) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). D. M. E. is funded by the UK Medical Research Council Unit grant MC_UU_12013_4, Australian Research Council Future Fellowship (FT130101709) and a NHMRC Senior Research Fellowship (GNT1137714). S. F. A. G. is funded by the Daniel B. Burke Endowed Chair for Diabetes Research and R01 HD056465. D. I. B. is supported by Spinozapremie (NWO-56-464-14192) and the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. M. I. M. is a Wellcome Senior Investgator and NIHR Senior Investigator supported by the Wellcome (090532, 098381, 203141), NIHR (NF-SI-0617-10090) and the US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MCiabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NLNIHR Biomedical Research Centre, Oxford. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
Published: 2019
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14. The UK10K project identifies rare variants in health and disease

Author: Walter, Klaudia, Min, Josine L., Huang, Jie, Crooks, Lucy, Memari, Yasin, McCarthy, Shane, Perry, John R. B., Xu, ChangJiang, Futema, Marta, Lawson, Daniel, Iotchkova, Valentina, Schiffels, Stephan, Hendricks, Audrey E., Danecek, Petr, Li, Rui, Floyd, James, Wain, Louise V., Barroso, Inês, Humphries, Steve E., Hurles, Matthew E., Zeggini, Eleftheria, Barrett, Jeffrey C., Plagnol, Vincent, Brent Richards, J., Greenwood, Celia M. T., Timpson, Nicholas J., Durbin, Richard, Soranzo, Nicole, Bala, Senduran, Clapham, Peter, Coates, Guy, Cox, Tony, Daly, Allan, Du, Yuanping, Edkins, Sarah, Ellis, Peter, Flicek, Paul, Guo, Xiaosen, Guo, Xueqin, Huang, Liren, Jackson, David K., Joyce, Chris, Keane, Thomas, Kolb-Kokocinski, Anja, Langford, Cordelia, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Maslen, John, Muddyman, Dawn, Quail, Michael A., Stalker, Jim, Sun, Jianping, Tian, Jing, Wang, Guangbiao, Wang, Jun, Wang, Yu, Wong, Kim, Zhang, Pingbo, Birney, Ewan, Boustred, Chris, Chen, Lu, Clement, Gail, Cocca, Massimiliano, Davey Smith, George, Day, Ian N. M., Day-Williams, Aaron, Down, Thomas, Dunham, Ian, Evans, David M., Gaunt, Tom R., Geihs, Matthias, Hart, Deborah, Howie, Bryan, Hubbard, Tim, Hysi, Pirro, Jamshidi, Yalda, Karczewski, Konrad J., Kemp, John P., Lachance, Genevieve, Lek, Monkol, Lopes, Margarida, MacArthur, Daniel G., Marchini, Jonathan, Mangino, Massimo, Mathieson, Iain, Metrustry, Sarah, Moayyeri, Alireza, Northstone, Kate, Panoutsopoulou, Kalliope, Paternoster, Lavinia, Quaye, Lydia, Ring, Susan, Ritchie, Graham R. S., Shihab, Hashem A., Shin, So-Youn, Small, Kerrin S., Soler Artigas, María, Southam, Lorraine, Spector, Timothy D., St Pourcain, Beate, Surdulescu, Gabriela, Tachmazidou, Ioanna, Tobin, Martin D., Valdes, Ana M., Visscher, Peter M., Ward, Kirsten, Wilson, Scott G., Yang, Jian, Zhang, Feng, Zheng, Hou-Feng, Anney, Richard, Ayub, Muhammad, Blackwood, Douglas, Bolton, Patrick F., Breen, Gerome, Collier, David A., Craddock, Nick, Curran, Sarah, Curtis, David, Gallagher, Louise, Geschwind, Daniel, Gurling, Hugh, Holmans, Peter, Lee, Irene, Lönnqvist, Jouko, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Morris, James, O'Donovan, Michael C., Owen, Michael J., Palotie, Aarno, Parr, Jeremy R., Paunio, Tiina, Pietilainen, Olli, Rehnström, Karola, Sharp, Sally I., Skuse, David, St Clair, David, Suvisaari, Jaana, Walters, James T. R., Williams, Hywel J., Bochukova, Elena, Bounds, Rebecca, Dominiczak, Anna, Farooqi, I. Sadaf, Keogh, Julia, Marenne, Gaëlle, Morris, Andrew, O'Rahilly, Stephen, Porteous, David J., Smith, Blair H., Wheeler, Eleanor, Al Turki, Saeed, Anderson, Carl A., Antony, Dinu, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Fitzpatrick, David R., Reghan Foley, A., Franklin, Christopher S., Grozeva, Detelina, Mitchison, Hannah M., Muntoni, Francesco, Onoufriadis, Alexandros, Parker, Victoria, Payne, Felicity, Lucy Raymond, F., Roberts, Nicola, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Spasic-Boskovic, Olivera, Stevens, Elizabeth, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Williamson, Kathleen A., Wilson, Crispian, Whyte, Tamieka, Ciampi, Antonio, Oualkacha, Karim, Bobrow, Martin, Griffin, Heather, Kaye, Jane, Kennedy, Karen, Kent, Alastair, Smee, Carol, Charlton, Ruth, Ekong, Rosemary, Khawaja, Farrah, Lopes, Luis R., Migone, Nicola, Payne, Stewart J., Pollitt, Rebecca C., Povey, Sue, Ridout, Cheryl K., Robinson, Rachel L., Scott, Richard H., Shaw, Adam, Syrris, Petros, Taylor, Rohan, Vandersteen, Anthony M., Amuzu, Antoinette, Pablo Casas, Juan, Chambers, John C., Dedoussis, George, Gambaro, Giovanni, Gasparini, Paolo, Isaacs, Aaron, Johnson, Jon, Kleber, Marcus E., Kooner, Jaspal S., Langenberg, Claudia, Luan, Jian'an, Malerba, Giovanni, März, Winfried, Matchan, Angela, Morris, Richard, Nordestgaard, Børge G., Benn, Marianne, Scott, Robert A., Toniolo, Daniela, Traglia, Michela, Tybjaerg-Hansen, Anne, van Duijn, Cornelia M., van Leeuwen, Elisabeth M., Varbo, Anette, Whincup, Peter, Zaza, Gianluigi, Zhang, Weihua, Civil Law, Epidemiology, Clinicum, Department of Psychiatry, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Broad Institute of MIT and Harvard, Palotie, Aarno, Walter, Klaudia, Min, Josine L., Huang, Jie, Crooks, Lucy, Memari, Yasin, Mccarthy, Shane, Perry, John R. B., Xu, Changjiang, Futema, Marta, Lawson, Daniel, Iotchkova, Valentina, Schiffels, Stephan, Hendricks, Audrey E., Danecek, Petr, Li, Rui, Floyd, Jame, Wain, Louise V., Barroso, Inê, Humphries, Steve E., Hurles, Matthew E., Zeggini, Eleftheria, Barrett, Jeffrey C., Plagnol, Vincent, Brent Richards, J., Greenwood, Celia M. T., Timpson, Nicholas J., Durbin, Richard, Soranzo, Nicole, Bala, Senduran, Clapham, Peter, Coates, Guy, Cox, Tony, Daly, Allan, Du, Yuanping, Edkins, Sarah, Ellis, Peter, Flicek, Paul, Guo, Xiaosen, Guo, Xueqin, Huang, Liren, Jackson, David K., Joyce, Chri, Keane, Thoma, Kolb Kokocinski, Anja, Langford, Cordelia, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Maslen, John, Muddyman, Dawn, Quail, Michael A., Stalker, Jim, Sun, Jianping, Tian, Jing, Wang, Guangbiao, Wang, Jun, Wang, Yu, Wong, Kim, Zhang, Pingbo, Birney, Ewan, Boustred, Chri, Chen, Lu, Clement, Gail, Cocca, Massimiliano, Davey Smith, George, Day, Ian N. M., Day Williams, Aaron, Down, Thoma, Dunham, Ian, Evans, David M., Gaunt, Tom R., Geihs, Matthia, Hart, Deborah, Howie, Bryan, Hubbard, Tim, Hysi, Pirro, Jamshidi, Yalda, Karczewski, Konrad J., Kemp, John P., Lachance, Genevieve, Lek, Monkol, Lopes, Margarida, Macarthur, Daniel G., Marchini, Jonathan, Mangino, Massimo, Mathieson, Iain, Metrustry, Sarah, Moayyeri, Alireza, Northstone, Kate, Panoutsopoulou, Kalliope, Paternoster, Lavinia, Quaye, Lydia, Ring, Susan, Ritchie, Graham R. S., Shihab, Hashem A., Shin, So Youn, Small, Kerrin S., Soler Artigas, María, Southam, Lorraine, Spector, Timothy D., St Pourcain, Beate, Surdulescu, Gabriela, Tachmazidou, Ioanna, Tobin, Martin D., Valdes, Ana M., Visscher, Peter M., Ward, Kirsten, Wilson, Scott G., Yang, Jian, Zhang, Feng, Zheng, Hou Feng, Anney, Richard, Ayub, Muhammad, Blackwood, Dougla, Bolton, Patrick F., Breen, Gerome, Collier, David A., Craddock, Nick, Curran, Sarah, Curtis, David, Gallagher, Louise, Geschwind, Daniel, Gurling, Hugh, Holmans, Peter, Lee, Irene, Lönnqvist, Jouko, Mcguffin, Peter, Mcintosh, Andrew M., Mckechanie, Andrew G., Mcquillin, Andrew, Morris, Jame, O'Donovan, Michael C., Owen, Michael J., Parr, Jeremy R., Paunio, Tiina, Pietilainen, Olli, Rehnström, Karola, Sharp, Sally I., Skuse, David, St Clair, David, Suvisaari, Jaana, Walters, James T. R., Williams, Hywel J., Bochukova, Elena, Bounds, Rebecca, Dominiczak, Anna, Farooqi, I. Sadaf, Keogh, Julia, Marenne, Gaëlle, Morris, Andrew, O'Rahilly, Stephen, Porteous, David J., Smith, Blair H., Wheeler, Eleanor, Al Turki, Saeed, Anderson, Carl A., Antony, Dinu, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Fitzpatrick, David R., Reghan Foley, A., Franklin, Christopher S., Grozeva, Detelina, Mitchison, Hannah M., Muntoni, Francesco, Onoufriadis, Alexandro, Parker, Victoria, Payne, Felicity, Lucy Raymond, F., Roberts, Nicola, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Spasic Boskovic, Olivera, Stevens, Elizabeth, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Williamson, Kathleen A., Wilson, Crispian, Whyte, Tamieka, Ciampi, Antonio, Oualkacha, Karim, Bobrow, Martin, Griffin, Heather, Kaye, Jane, Kennedy, Karen, Kent, Alastair, Smee, Carol, Charlton, Ruth, Ekong, Rosemary, Khawaja, Farrah, Lopes, Luis R., Migone, Nicola, Payne, Stewart J., Pollitt, Rebecca C., Povey, Sue, Ridout, Cheryl K., Robinson, Rachel L., Scott, Richard H., Shaw, Adam, Syrris, Petro, Taylor, Rohan, Vandersteen, Anthony M., Amuzu, Antoinette, Pablo Casas, Juan, Chambers, John C., Dedoussis, George, Gambaro, Giovanni, Gasparini, Paolo, Isaacs, Aaron, Johnson, Jon, Kleber, Marcus E., Kooner, Jaspal S., Langenberg, Claudia, Luan, Jian'An, Malerba, Giovanni, März, Winfried, Matchan, Angela, Morris, Richard, Nordestgaard, Børge G., Benn, Marianne, Scott, Robert A., Toniolo, Daniela, Traglia, Michela, Tybjaerg Hansen, Anne, van Duijn, Cornelia M., van Leeuwen, Elisabeth M., Varbo, Anette, Whincup, Peter, Zaza, Gianluigi, and Zhang, Weihua
Subjects: APOC3, Male, Genome-wide association study, genetics,UK10K,Whole-genome sequencing, Genome-wide association studies, Next-generation sequencing, Genome-wide association studies, rare and low-frequency variants, Cohort Studies, OF-FUNCTION MUTATIONS, genetics, Disease, Exome, Exome sequencing, POPULATION, Genetics, education.field_of_study, Multidisciplinary, HERITABILITY, Great Britain, Genomics, Reference Standards, Multidisciplinary Sciences, Health, Science & Technology - Other Topics, INCIDENTAL FINDINGS, LOW-FREQUENCY, Female, Adiponectin, General Science & Technology, Genetics, Medical, Population, Computational biology, Biology, Article, MD Multidisciplinary, SEQUENCE VARIATION, UK10K Consortium, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, COMMON, Alleles, Triglycerides, Genetic association, Whole genome sequencing, Whole-genome sequencing, Science & Technology, Genome, Human, COMPLEX TRAITS, Genetic Variation, Molecular Sequence Annotation, Sequence Analysis, DNA, Lipid Metabolism, United Kingdom, 3141 Health care science, Genetics, Population, UK10K, Receptors, LDL, Next-generation sequencing, rare and low-frequency variants, Imputation (genetics), Genome-Wide Association Study
Abstract: M. Kivimäki työryhmäjäsen. The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
Published: 2015
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15. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author: Zheng, Hou-Feng, Forgetta, Vincenzo, Hsu, Yi-Hsiang, Estrada, Karol, Rosello-Diez, Alberto, Leo, Paul J, Dahia, Chitra L, Park-Min, Kyung Hyun, Tobias, Jonathan H, Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching-Ti, Uggla, Charlotta, Evans, Daniel S, Nielson, Carrie M, Walter, Klaudia, Pettersson-Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen-Chi, Mokry, Lauren E, Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia-Ho, Cheung, Warren, Medina-Gómez, Carolina, Ge, Bing, Chen, Shu-Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A, Gregson, Celia L, Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J, Marshall, Mhairi, Gardiner, Brooke B, Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y, Thorleifsson, Gudmar, Enneman, Anke W, van Schoor, Natasja M, de Groot, Lisette CPGM, van der Velde, Nathalie, Melin, Beatrice, Kemp, John P, Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G, Williams, Stephen R, Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z, Haessler, Jeff, Chasman, Daniel I, Giulianini, Franco, Rose, Lynda M, Ridker, Paul M, Eisman, John A, Nguyen, Tuan V, Center, Jacqueline R, Nogues, Xavier, Garcia-Giralt, Natalia, Launer, Lenore L, Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M, Karlsson, Magnus K, Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, Arp, Pascal P, Koromani, Fjorda, Prince, Richard L, Lewis, Joshua R, Langdahl, Bente L, Hermann, A Pernille, Jensen, Jens-Erik B, Kaptoge, Stephen, Khaw, Kay-Tee, Reeve, Jonathan, Formosa, Melissa M, Xuereb-Anastasi, Angela, Åkesson, Kristina, McGuigan, Fiona E, Garg, Gaurav, Olmos, Jose M, Zarrabeitia, Maria T, Riancho, Jose A, Ralston, Stuart H, Alonso, Nerea, Jiang, Xi, Goltzman, David, Pastinen, Tomi, Grundberg, Elin, Gauguier, Dominique, Orwoll, Eric S, Karasik, David, Davey-Smith, George, AOGC Consortium, Smith, Albert V, Siggeirsdottir, Kristin, Harris, Tamara B, Zillikens, M Carola, van Meurs, Joyce BJ, Thorsteinsdottir, Unnur, Maurano, Matthew T, Timpson, Nicholas J, Soranzo, Nicole, Durbin, Richard, Wilson, Scott G, Ntzani, Evangelia E, Brown, Matthew A, Stefansson, Kari, Hinds, David A, Spector, Tim, Cupples, L Adrienne, Ohlsson, Claes, Greenwood, Celia MT, UK10K Consortium, Jackson, Rebecca D, Rowe, David W, Loomis, Cynthia A, Evans, David M, Ackert-Bicknell, Cheryl L, Joyner, Alexandra L, Duncan, Emma L, Kiel, Douglas P, Rivadeneira, Fernando, and Richards, J Brent
Subjects: Homeodomain Proteins, Genotype, Genome, Human, General Science & Technology, European Continental Ancestry Group, Genetic Variation, Sequence Analysis, DNA, Genomics, Bone and Bones, Europe, Wnt Proteins, Mice, Disease Models, Animal, Fractures, Bone, AOGC Consortium, Gene Frequency, Bone Density, MD Multidisciplinary, UK10K Consortium, Animals, Humans, Genetic Predisposition to Disease, Female, Exome
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 ncontrols = 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 reference panels to study the genetic architecture of complex traits and disease in the general population.
Published: 2015
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16. Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder

Author: de Moor, Marleen H.M., van den Berg, Stéphanie M., Verweij, Karin J.H., Krueger, Robert F., Luciano, Michelle, Vasquez, Alejandro Arias, Matteson, Lindsay K., Derringer, Jaime, Esko, Tõnu, Amin, Najaf, Gordon, Scott D., Hansell, Narelle K., Hart, Amy B., Seppälä, Ilkka, Huffman, Jennifer E., Konte, Bettina, Lahti, Jari, Lee, Minyoung, Miller, Mike, Nutile, Teresa, Tanaka, Toshiko, Teumer, Alexander, Viktorin, Alexander, Wedenoja, Juho, Abecasis, Goncalo R., Adkins, Daniel E., Agrawal, Arpana, Allik, Jüri, Appel, Katja, Bigdeli, Timothy B., Busonero, Fabio, Campbell, Harry, Costa, Paul T., Smith, George Davey, Davies, Gail, de Wit, Harriet, Ding, Jun, Engelhardt, Barbara E., Eriksson, Johan G., Fedko, Iryna O., Ferrucci, Luigi, Franke, Barbara, Giegling, Ina, Grucza, Richard, Hartmann, Annette M., Heath, Andrew C., Heinonen, Kati, Henders, Anjali K., Homuth, Georg, Hottenga, Jouke-Jan, Janzing, Joost, Jokela, Markus, Karlsson, Robert, Kemp, John P., Kirkpatrick, Matthew G., Latvala, Antti, Lehtimäki, Terho, Liewald, David C., Madden, Pamela A.F., Magri, Chiara, Magnusson, Patrik K.E., Marten, Jonathan, Maschio, Andrea, Medland, Sarah E., Mihailov, Evelin, Milaneschi, Yuri, Montgomery, Grant W., Nauck, Matthias, Ouwens, Klaasjan G., Palotie, Aarno, Pettersson, Erik, Polasek, Ozren, Qian, Yong, Pulkki-Råback, Laura, Raitakari, Olli T., Realo, Anu, Rose, Richard J., Ruggiero, Daniela, Schmidt, Carsten O., Slutske, Wendy S., Sorice, Rossella, Starr, John M., Pourcain, Beate St, Sutin, Angelina R., Timpson, Nicholas J., Trochet, Holly, Vermeulen, Sita, Vuoksimaa, Eero, Widen, Elisabeth, Wouda, Jasper, Wright, Margaret J., Zgaga, Lina, Scotland, Generation, Porteous, David, Minelli, Alessandra, Palmer, Abraham A., Rujescu, Dan, Ciullo, Marina, Hayward, Caroline, Rudan, Igor, Metspalu, Andres, Kaprio, Jaakko, Deary, Ian J., Räikkönen, Katri, Wilson, James F., Keltikangas-Järvinen, Liisa, Bierut, Laura J., Hettema, John M., Grabe, Hans J., van Duijn, Cornelia M., Evans, David M., Schlessinger, David, Pedersen, Nancy L., Terracciano, Antonio, McGue, Matt, Penninx, Brenda W.J.H., Martin, Nicholas G., and Boomsma, Dorret I.
Subjects: Neuroticism, Depressive Disorder, Major, Multifactorial Inheritance, Cell Adhesion Molecules, Neuronal, Anxiety Disorders, Polymorphism, Single Nucleotide, Article, Risk Factors, Humans, Genetic Predisposition to Disease, Cell Adhesion Molecules, Guanylate Kinases, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, Personality
Abstract: Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases).To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD.Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014.Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 P .05) and MDD (4.02 × 10-9 P .05) in the 2 other cohorts.This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.
Published: 2015

17. Genetic variation in protein specific antigen detected prostate cancer and the effect of control selection on genetic association studies

Author: Knipe, Duleeka W, Evans, David M, Kemp, John P., Eeles, Rosalind, Easton, Douglas F, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Donovan, Jenny L., Hamdy, Freddie C., Neal, David E, Smith, George Davey, Lathrop, Mark, and Martin, Richard M
Subjects: Male, Genotype, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Middle Aged, Prostate-Specific Antigen, Polymorphism, Single Nucleotide, Article, Genetic Association Studies, Aged
Abstract: Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls.We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA0.5 ng/mL) or "high" (PSA ≥ 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA.The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates0.04). We found a novel inverse association of rs9311171-T with circulating PSA.Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA.These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria.
Published: 2014

18. Common variation near ROBO2 is associated with expressive vocabulary in infancy

Author: St Pourcain, Beate, Cents, Rolieke A.M., Whitehouse, Andrew J.O., Haworth, Claire M.A., Davis, Oliver S.P., O'Reilly, Paul F., Roulstone, Susan, Wren, Yvonne, Ang, Qi W., Velders, Fleur P., Evans, David M., Kemp, John P., Warrington, Nicole M., Miller, Laura, Timpson, Nicholas J., Ring, Susan M., Verhulst, Frank C., Hofman, Albert, Rivadeneira, Fernando, Meaburn, Emma L., Price, Thomas S., Dale, Philip S., Pillas, Demetris, Yliherva, Anneli, Rodriguez, Alina, Golding, Jean, Jaddoe, Vincent W.v., Jarvelin, Marjo-riitta, Plomin, Robert, Pennell, Craig E., Tiemeier, Henning, Davey Smith, George, Child and Adolescent Psychiatry / Psychology, Epidemiology, Internal Medicine, and Erasmus MC other
Subjects: Male, Genetic Linkage, European Continental Ancestry Group, Quantitative Trait Loci, Gene Expression, CHROMOSOME-3, Language Development, Polymorphism, Single Nucleotide, Speech Sound Disorder, Vocabulary, White People, Article, psyc, Dyslexia, C841 Health Psychology, MD Multidisciplinary, TOOL, Humans, Speech, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, AUTISM, Autistic Disorder, Receptors, Immunologic, LANGUAGE-DEVELOPMENT SURVEY, AXON-GUIDANCE RECEPTORS, GENE-EXPRESSION, Language, Language Disorders, Science & Technology, Chromosome Mapping, Infant, GENOTYPES, C420 Human Genetics, P1, Multidisciplinary Sciences, ENHANCERS, Phenotype, Child, Preschool, MIDLINE, Science & Technology - Other Topics, Female, Genome-Wide Association Study
Abstract: Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology consortium, analysing an early (15–18 months, ‘one-word stage’, NTotal=8,889) and a later (24–30 months, ‘two-word stage’, NTotal=10,819) phase of language acquisition. For the early phase, one single-nucleotide polymorphism (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon-binding receptor, reaches the genome-wide significance level (P=1.3 × 10−8) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by genome-wide complex trait analysis (meta-GCTA h215–18-months=0.13, meta-GCTA h224–30-months=0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h224-months=0.20)., The genetic basis of expressive vocabulary in children around 2 years old is poorly understood. Here, the authors show that a genetic variant near the ROBO2 gene is associated with early language acquisition in the general population and highlight a potential genetic link between language-related common genetic variation and a linkage region for dyslexia, speech-sound disorder and reading.
Published: 2014
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19. Mining the human phenome using allelic scores that index biological intermediates

Author: Brion, Marie Jo A., Evans, David M., Paternoster, Lavinia, Kemp, John P., McMahon, George, Munafò, Marcus, Whitfield, John B., Medland, Sarah E., Montgomery, Grant W., Timpson, Nicholas J., St. Pourcain, Beate, Lawlor, Debbie A., Martin, Nicholas G., Dehghan, Abbas, Hirschhorn, Joel, Davey Smith, George, and Conway, David I.
Subjects: Phenotype, Genotype, Genome, Human, Humans, Genetic Predisposition to Disease, Adaptor Proteins, Vesicular Transport/genetics, Genetic Diseases, Inborn/genetics, Longitudinal Studies, C-Reactive Protein/genetics, Polymorphism, Single Nucleotide/genetics, Alleles, Genome-Wide Association Study
Abstract: It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
Published: 2013
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20. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

Author: Cheng, Ching-Yu, Schache, Maria, Ikram, M Kamran, Young, Terri L, Guggenheim, Jeremy A, Vitart, Veronique, MacGregor, Stuart, Verhoeven, Virginie JM, Barathi, Veluchamy A, Liao, Jiemin, Hysi, Pirro G, Bailey-Wilson, Joan E, St Pourcain, Beate, Kemp, John P, McMahon, George, Timpson, Nicholas J, Evans, David M, Montgomery, Grant W, Mishra, Aniket, Wang, Ya Xing, Wang, Jie Jin, Rochtchina, Elena, Polasek, Ozren, Wright, Alan F, Amin, Najaf, van Leeuwen, Elisabeth M, Wilson, James F, Pennell, Craig E, van Duijn, Cornelia M, de Jong, Paulus TVM, Vingerling, Johannes R, Zhou, Xin, Chen, Peng, Li, Ruoying, Tay, Wan-Ting, Zheng, Yingfeng, Chew, Merwyn, Consortium for Refractive Error and Myopia, Burdon, Kathryn P, Craig, Jamie E, Iyengar, Sudha K, Igo, Robert P, Lass, Jonathan H, Fuchs' Genetics Multi-Center Study Group, Chew, Emily Y, Haller, Toomas, Mihailov, Evelin, Metspalu, Andres, Wedenoja, Juho, Simpson, Claire L, Wojciechowski, Robert, Höhn, René, Mirshahi, Alireza, Zeller, Tanja, Pfeiffer, Norbert, Lackner, Karl J, Wellcome Trust Case Control Consortium 2, Bettecken, Thomas, Meitinger, Thomas, Oexle, Konrad, Pirastu, Mario, Portas, Laura, Nag, Abhishek, Williams, Katie M, Yonova-Doing, Ekaterina, Klein, Ronald, Klein, Barbara E, Hosseini, S Mohsen, Paterson, Andrew D, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, and Complications Research Group, Makela, Kari-Matti, Lehtimaki, Terho, Kahonen, Mika, Raitakari, Olli, Yoshimura, Nagahisa, Matsuda, Fumihiko, Chen, Li Jia, Pang, Chi Pui, Yip, Shea Ping, Yap, Maurice KH, Meguro, Akira, Mizuki, Nobuhisa, Inoko, Hidetoshi, Foster, Paul J, Zhao, Jing Hua, Vithana, Eranga, Tai, E-Shyong, Fan, Qiao, Xu, Liang, Campbell, Harry, Fleck, Brian, Rudan, Igor, Aung, Tin, Hofman, Albert, Uitterlinden, André G, Bencic, Goran, Khor, Chiea-Chuen, Forward, Hannah, Pärssinen, Olavi, and Mitchell, Paul
Subjects: Adult, Male, Adolescent, Gene Expression, Eye, Medical and Health Sciences, White People, Asian People, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Axial Length, Polymorphism, Aetiology, Eye Proteins, Eye Disease and Disorders of Vision, Aged, Genetics & Heredity, Consortium for Refractive Error and Myopia, Wellcome Trust Case Control Consortium 2, Human Genome, Single Nucleotide, Middle Aged, Biological Sciences, and Complications Research Group, Refractive Errors, Fuchs' Genetics Multi-Center Study Group, Genetic Loci, Female, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, Signal Transduction, Genome-Wide Association Study
Abstract: Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
Published: 2013

21. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author: Steinthorsdottir, Valgerdur, McGinnis, Ralph, Williams, Nicholas O, Stefansdottir, Lilja, Thorleifsson, Gudmar, Shooter, Scott, Fadista, João, Sigurdsson, Jon K, Auro, Kirsi M, Berezina, Galina, Borges, Maria-Carolina, Bumpstead, Suzannah, Bybjerg-Grauholm, Jonas, Colgiu, Irina, Dolby, Vivien A, Dudbridge, Frank, Engel, Stephanie M, Franklin, Christopher S, Frigge, Michael L, Frisbaek, Yr, Geirsson, Reynir T, Geller, Frank, Gretarsdottir, Solveig, Gudbjartsson, Daniel F, Harmon, Quaker, Hougaard, David Michael, Hegay, Tatyana, Helgadottir, Anna, Hjartardottir, Sigrun, Jääskeläinen, Tiina, Johannsdottir, Hrefna, Jonsdottir, Ingileif, Juliusdottir, Thorhildur, Kalsheker, Noor, Kasimov, Abdumadjit, Kemp, John P, Kivinen, Katja, Klungsøyr, Kari, Lee, Wai K, Melbye, Mads, Miedzybrodska, Zosia, Moffett, Ashley, Najmutdinova, Dilbar, Nishanova, Firuza, Olafsdottir, Thorunn, Perola, Markus, Pipkin, Fiona Broughton, Poston, Lucilla, Prescott, Gordon, Saevarsdottir, Saedis, Salimbayeva, Damilya, Scaife, Paula Juliet, Skotte, Line, Staines-Urias, Eleonora, Stefansson, Olafur A, Sørensen, Karina Meden, Thomsen, Liv Cecilie Vestrheim, Tragante, Vinicius, Trogstad, Lill, Simpson, Nigel AB, FINNPEC Consortium, GOPEC Consortium, Aripova, Tamara, Casas, Juan P, Dominiczak, Anna F, Walker, James J, Thorsteinsdottir, Unnur, Iversen, Ann-Charlotte, Feenstra, Bjarke, Lawlor, Deborah A, Boyd, Heather Allison, Magnus, Per, Laivuori, Hannele, Zakhidova, Nodira, Svyatova, Gulnara, Stefansson, Kari, and Morgan, Linda
Subjects: Adult, Multifactorial Inheritance, Fibroblast Growth Factor 5, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Datasets as Topic, Blood Pressure, Pre-Eclampsia, Pregnancy, Humans, Genetic Predisposition to Disease, Prospective Studies, reproductive and urinary physiology, Adaptor Proteins, Signal Transducing, Aged, 2. Zero hunger, Hypertension, Pregnancy-Induced, Middle Aged, female genital diseases and pregnancy complications, MDS1 and EVI1 Complex Locus Protein, 3. Good health, Europe, Genetic Loci, Case-Control Studies, embryonic structures, Asia, Central, Female, Genome-Wide Association Study
Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

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21 results on '"Kemp, John P."'

1. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

2. An atlas of genetic influences on osteoporosis in humans and mice.

3. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

4. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

5. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

6. Genetic variation in prostate-specific antigen-detected prostate cancer and the effect of control selection on genetic association studies.

7. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

8. Whole‐genome sequencing identifies EN1 as a determinant of bone density and fracture

9. Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

10. Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder.

11. A genome-wide association meta-analysis identifies new childhood obesity loci

12. An atlas of genetic influences on osteoporosis in humans and mice

13. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

14. The UK10K project identifies rare variants in health and disease

15. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

16. Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder

17. Genetic variation in protein specific antigen detected prostate cancer and the effect of control selection on genetic association studies

18. Common variation near ROBO2 is associated with expressive vocabulary in infancy

19. Mining the human phenome using allelic scores that index biological intermediates

20. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

21. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

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