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Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.
Irvin MR, Sitlani CM, Floyd JS, Psaty BM, Bis JC, Wiggins KL, Whitsel EA, Sturmer T, Stewart J, Raffield L, Sun F, Liu CT, Xu H, Cupples AL, Tanner RM, Rossing P, Smith A, Zilhão NR, Launer LJ, Noordam R, Rotter JI, Yao J, Li X, Guo X, Limdi N, Sundaresan A, Lange L, Correa A, Stott DJ, Ford I, Jukema JW, Gudnason V, Mook-Kanamori DO, Trompet S, Palmas W, Warren HR, Hellwege JN, Giri A, O'donnell C, Hung AM, Edwards TL, Ahluwalia TS, Arnett DK, Avery CL
(2019) Am J Hypertens 32: 1146-1153
MeSH Terms: African Americans, Aged, Antihypertensive Agents, Blood Pressure, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Drug Resistance, Dystrophin-Associated Proteins, Europe, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Myosin Heavy Chains, Myosin Type V, Neuropeptides, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Transcription Factors, United States
Show Abstract · Added March 3, 2020
BACKGROUND - Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.
METHODS - We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.
RESULTS - The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.
CONCLUSION - This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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28 MeSH Terms
Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.
Hellwege JN, Velez Edwards DR, Giri A, Qiu C, Park J, Torstenson ES, Keaton JM, Wilson OD, Robinson-Cohen C, Chung CP, Roumie CL, Klarin D, Damrauer SM, DuVall SL, Siew E, Akwo EA, Wuttke M, Gorski M, Li M, Li Y, Gaziano JM, Wilson PWF, Tsao PS, O'Donnell CJ, Kovesdy CP, Pattaro C, Köttgen A, Susztak K, Edwards TL, Hung AM
(2019) Nat Commun 10: 3842
MeSH Terms: Adult, Aged, Animals, Cell Line, Chromosome Mapping, Cohort Studies, Computational Biology, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, RNA-Seq, Renal Insufficiency, Chronic, Transcriptome, United States, United States Department of Veterans Affairs, Veterans
Show Abstract · Added March 3, 2020
Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.
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MeSH Terms
Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, Ntritsos G, Dimou N, Cabrera CP, Karaman I, Ng FL, Evangelou M, Witkowska K, Tzanis E, Hellwege JN, Giri A, Velez Edwards DR, Sun YV, Cho K, Gaziano JM, Wilson PWF, Tsao PS, Kovesdy CP, Esko T, Mägi R, Milani L, Almgren P, Boutin T, Debette S, Ding J, Giulianini F, Holliday EG, Jackson AU, Li-Gao R, Lin WY, Luan J, Mangino M, Oldmeadow C, Prins BP, Qian Y, Sargurupremraj M, Shah N, Surendran P, Thériault S, Verweij N, Willems SM, Zhao JH, Amouyel P, Connell J, de Mutsert R, Doney ASF, Farrall M, Menni C, Morris AD, Noordam R, Paré G, Poulter NR, Shields DC, Stanton A, Thom S, Abecasis G, Amin N, Arking DE, Ayers KL, Barbieri CM, Batini C, Bis JC, Blake T, Bochud M, Boehnke M, Boerwinkle E, Boomsma DI, Bottinger EP, Braund PS, Brumat M, Campbell A, Campbell H, Chakravarti A, Chambers JC, Chauhan G, Ciullo M, Cocca M, Collins F, Cordell HJ, Davies G, de Borst MH, de Geus EJ, Deary IJ, Deelen J, Del Greco M F, Demirkale CY, Dörr M, Ehret GB, Elosua R, Enroth S, Erzurumluoglu AM, Ferreira T, Frånberg M, Franco OH, Gandin I, Gasparini P, Giedraitis V, Gieger C, Girotto G, Goel A, Gow AJ, Gudnason V, Guo X, Gyllensten U, Hamsten A, Harris TB, Harris SE, Hartman CA, Havulinna AS, Hicks AA, Hofer E, Hofman A, Hottenga JJ, Huffman JE, Hwang SJ, Ingelsson E, James A, Jansen R, Jarvelin MR, Joehanes R, Johansson Å, Johnson AD, Joshi PK, Jousilahti P, Jukema JW, Jula A, Kähönen M, Kathiresan S, Keavney BD, Khaw KT, Knekt P, Knight J, Kolcic I, Kooner JS, Koskinen S, Kristiansson K, Kutalik Z, Laan M, Larson M, Launer LJ, Lehne B, Lehtimäki T, Liewald DCM, Lin L, Lind L, Lindgren CM, Liu Y, Loos RJF, Lopez LM, Lu Y, Lyytikäinen LP, Mahajan A, Mamasoula C, Marrugat J, Marten J, Milaneschi Y, Morgan A, Morris AP, Morrison AC, Munson PJ, Nalls MA, Nandakumar P, Nelson CP, Niiranen T, Nolte IM, Nutile T, Oldehinkel AJ, Oostra BA, O'Reilly PF, Org E, Padmanabhan S, Palmas W, Palotie A, Pattie A, Penninx BWJH, Perola M, Peters A, Polasek O, Pramstaller PP, Nguyen QT, Raitakari OT, Ren M, Rettig R, Rice K, Ridker PM, Ried JS, Riese H, Ripatti S, Robino A, Rose LM, Rotter JI, Rudan I, Ruggiero D, Saba Y, Sala CF, Salomaa V, Samani NJ, Sarin AP, Schmidt R, Schmidt H, Shrine N, Siscovick D, Smith AV, Snieder H, Sõber S, Sorice R, Starr JM, Stott DJ, Strachan DP, Strawbridge RJ, Sundström J, Swertz MA, Taylor KD, Teumer A, Tobin MD, Tomaszewski M, Toniolo D, Traglia M, Trompet S, Tuomilehto J, Tzourio C, Uitterlinden AG, Vaez A, van der Most PJ, van Duijn CM, Vergnaud AC, Verwoert GC, Vitart V, Völker U, Vollenweider P, Vuckovic D, Watkins H, Wild SH, Willemsen G, Wilson JF, Wright AF, Yao J, Zemunik T, Zhang W, Attia JR, Butterworth AS, Chasman DI, Conen D, Cucca F, Danesh J, Hayward C, Howson JMM, Laakso M, Lakatta EG, Langenberg C, Melander O, Mook-Kanamori DO, Palmer CNA, Risch L, Scott RA, Scott RJ, Sever P, Spector TD, van der Harst P, Wareham NJ, Zeggini E, Levy D, Munroe PB, Newton-Cheh C, Brown MJ, Metspalu A, Hung AM, O'Donnell CJ, Edwards TL, Psaty BM, Tzoulaki I, Barnes MR, Wain LV, Elliott P, Caulfield MJ, Million Veteran Program
(2018) Nat Genet 50: 1412-1425
MeSH Terms: Adult, Aged, Aged, 80 and over, Blood Pressure, Cardiovascular Diseases, Cells, Cultured, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Testing, Genetics, Population, Genome-Wide Association Study, Human Umbilical Vein Endothelial Cells, Humans, Hypertension, Life Style, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors
Show Abstract · Added March 3, 2020
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.
Sung YJ, Winkler TW, de Las Fuentes L, Bentley AR, Brown MR, Kraja AT, Schwander K, Ntalla I, Guo X, Franceschini N, Lu Y, Cheng CY, Sim X, Vojinovic D, Marten J, Musani SK, Li C, Feitosa MF, Kilpeläinen TO, Richard MA, Noordam R, Aslibekyan S, Aschard H, Bartz TM, Dorajoo R, Liu Y, Manning AK, Rankinen T, Smith AV, Tajuddin SM, Tayo BO, Warren HR, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris SE, Hartwig FP, Horimoto ARVR, Hsu FC, Jackson AU, Kähönen M, Kasturiratne A, Kühnel B, Leander K, Lee WJ, Lin KH, 'an Luan J, McKenzie CA, Meian H, Nelson CP, Rauramaa R, Schupf N, Scott RA, Sheu WHH, Stančáková A, Takeuchi F, van der Most PJ, Varga TV, Wang H, Wang Y, Ware EB, Weiss S, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking D, Aung T, Barr RG, Bielak LF, Boerwinkle E, Bottinger EP, Braund PS, Brody JA, Broeckel U, Cabrera CP, Cade B, Caizheng Y, Campbell A, Canouil M, Chakravarti A, CHARGE Neurology Working Group, Chauhan G, Christensen K, Cocca M, COGENT-Kidney Consortium, Collins FS, Connell JM, de Mutsert R, de Silva HJ, Debette S, Dörr M, Duan Q, Eaton CB, Ehret G, Evangelou E, Faul JD, Fisher VA, Forouhi NG, Franco OH, Friedlander Y, Gao H, GIANT Consortium, Gigante B, Graff M, Gu CC, Gu D, Gupta P, Hagenaars SP, Harris TB, He J, Heikkinen S, Heng CK, Hirata M, Hofman A, Howard BV, Hunt S, Irvin MR, Jia Y, Joehanes R, Justice AE, Katsuya T, Kaufman J, Kerrison ND, Khor CC, Koh WP, Koistinen HA, Komulainen P, Kooperberg C, Krieger JE, Kubo M, Kuusisto J, Langefeld CD, Langenberg C, Launer LJ, Lehne B, Lewis CE, Li Y, Lifelines Cohort Study, Lim SH, Lin S, Liu CT, Liu J, Liu J, Liu K, Liu Y, Loh M, Lohman KK, Long J, Louie T, Mägi R, Mahajan A, Meitinger T, Metspalu A, Milani L, Momozawa Y, Morris AP, Mosley TH, Munson P, Murray AD, Nalls MA, Nasri U, Norris JM, North K, Ogunniyi A, Padmanabhan S, Palmas WR, Palmer ND, Pankow JS, Pedersen NL, Peters A, Peyser PA, Polasek O, Raitakari OT, Renström F, Rice TK, Ridker PM, Robino A, Robinson JG, Rose LM, Rudan I, Sabanayagam C, Salako BL, Sandow K, Schmidt CO, Schreiner PJ, Scott WR, Seshadri S, Sever P, Sitlani CM, Smith JA, Snieder H, Starr JM, Strauch K, Tang H, Taylor KD, Teo YY, Tham YC, Uitterlinden AG, Waldenberger M, Wang L, Wang YX, Wei WB, Williams C, Wilson G, Wojczynski MK, Yao J, Yuan JM, Zonderman AB, Becker DM, Boehnke M, Bowden DW, Chambers JC, Chen YI, de Faire U, Deary IJ, Esko T, Farrall M, Forrester T, Franks PW, Freedman BI, Froguel P, Gasparini P, Gieger C, Horta BL, Hung YJ, Jonas JB, Kato N, Kooner JS, Laakso M, Lehtimäki T, Liang KW, Magnusson PKE, Newman AB, Oldehinkel AJ, Pereira AC, Redline S, Rettig R, Samani NJ, Scott J, Shu XO, van der Harst P, Wagenknecht LE, Wareham NJ, Watkins H, Weir DR, Wickremasinghe AR, Wu T, Zheng W, Kamatani Y, Laurie CC, Bouchard C, Cooper RS, Evans MK, Gudnason V, Kardia SLR, Kritchevsky SB, Levy D, O'Connell JR, Psaty BM, van Dam RM, Sims M, Arnett DK, Mook-Kanamori DO, Kelly TN, Fox ER, Hayward C, Fornage M, Rotimi CN, Province MA, van Duijn CM, Tai ES, Wong TY, Loos RJF, Reiner AP, Rotter JI, Zhu X, Bierut LJ, Gauderman WJ, Caulfield MJ, Elliott P, Rice K, Munroe PB, Morrison AC, Cupples LA, Rao DC, Chasman DI
(2018) Am J Hum Genet 102: 375-400
MeSH Terms: Blood Pressure, Cohort Studies, Continental Population Groups, Diastole, Epistasis, Genetic, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Smoking, Systole
Show Abstract · Added April 10, 2018
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Copyright © 2018 American Society of Human Genetics. All rights reserved.
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15 MeSH Terms
Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations.
Hong J, Hatchell KE, Bradfield JP, Bjonnes A, Chesi A, Lai CQ, Langefeld CD, Lu L, Lu Y, Lutsey PL, Musani SK, Nalls MA, Robinson-Cohen C, Roizen JD, Saxena R, Tucker KL, Ziegler JT, Arking DE, Bis JC, Boerwinkle E, Bottinger EP, Bowden DW, Gilsanz V, Houston DK, Kalkwarf HJ, Kelly A, Lappe JM, Liu Y, Michos ED, Oberfield SE, Palmer ND, Rotter JI, Sapkota B, Shepherd JA, Wilson JG, Basu S, de Boer IH, Divers J, Freedman BI, Grant SFA, Hakanarson H, Harris TB, Kestenbaum BR, Kritchevsky SB, Loos RJF, Norris JM, Norwood AF, Ordovas JM, Pankow JS, Psaty BM, Sanghera DK, Wagenknecht LE, Zemel BS, Meigs J, Dupuis J, Florez JC, Wang T, Liu CT, Engelman CD, Billings LK
(2018) J Clin Endocrinol Metab 103: 1380-1392
MeSH Terms: Adolescent, Adult, African Americans, Aged, Body Mass Index, Child, European Continental Ancestry Group, Female, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, United States, Vitamin D, Vitamin D Deficiency, Young Adult
Show Abstract · Added January 3, 2019
Context - Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry.
Objective - The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries.
Design - Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL).
Patients or Other Participants - In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study.
Main Outcome Measures - Blood concentrations of 25(OH)D were measured for all participants.
Results - Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.
Conclusions - Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.
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Association analysis identifies 65 new breast cancer risk loci.
Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, Lemaçon A, Soucy P, Glubb D, Rostamianfar A, Bolla MK, Wang Q, Tyrer J, Dicks E, Lee A, Wang Z, Allen J, Keeman R, Eilber U, French JD, Qing Chen X, Fachal L, McCue K, McCart Reed AE, Ghoussaini M, Carroll JS, Jiang X, Finucane H, Adams M, Adank MA, Ahsan H, Aittomäki K, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Arun B, Auer PL, Bacot F, Barrdahl M, Baynes C, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Brinton L, Broberg P, Brock IW, Broeks A, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Butterbach K, Cai Q, Cai H, Caldés T, Canzian F, Carracedo A, Carter BD, Castelao JE, Chan TL, David Cheng TY, Seng Chia K, Choi JY, Christiansen H, Clarke CL, NBCS Collaborators, Collée M, Conroy DM, Cordina-Duverger E, Cornelissen S, Cox DG, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Elvira M, Engel C, Eriksson M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gaborieau V, Gabrielson M, Gago-Dominguez M, Gao YT, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hamel N, Hankinson S, Harrington P, Hart SN, Hartikainen JM, Hartman M, Hein A, Heyworth J, Hicks B, Hillemanns P, Ho DN, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Hou MF, Hsiung CN, Huang G, Humphreys K, Ishiguro J, Ito H, Iwasaki M, Iwata H, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kasuga Y, Kerin MJ, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Kosma VM, Kristensen VN, Krüger U, Kwong A, Lambrechts D, Le Marchand L, Lee E, Lee MH, Lee JW, Neng Lee C, Lejbkowicz F, Li J, Lilyquist J, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Lophatananon A, Lubinski J, Luccarini C, Lux MP, Ma ESK, MacInnis RJ, Maishman T, Makalic E, Malone KE, Kostovska IM, Mannermaa A, Manoukian S, Manson JE, Margolin S, Mariapun S, Martinez ME, Matsuo K, Mavroudis D, McKay J, McLean C, Meijers-Heijboer H, Meindl A, Menéndez P, Menon U, Meyer J, Miao H, Miller N, Taib NAM, Muir K, Mulligan AM, Mulot C, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Noh DY, Nordestgaard BG, Norman A, Olopade OI, Olson JE, Olsson H, Olswold C, Orr N, Pankratz VS, Park SK, Park-Simon TW, Lloyd R, Perez JIA, Peterlongo P, Peto J, Phillips KA, Pinchev M, Plaseska-Karanfilska D, Prentice R, Presneau N, Prokofyeva D, Pugh E, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Ruddy KJ, Rüdiger T, Rudolph A, Ruebner M, Rutgers EJT, Saloustros E, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Scott RJ, Scott C, Seal S, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng G, Sherman ME, Shrubsole MJ, Shu XO, Smeets A, Sohn C, Southey MC, Spinelli JJ, Stegmaier C, Stewart-Brown S, Stone J, Stram DO, Surowy H, Swerdlow A, Tamimi R, Taylor JA, Tengström M, Teo SH, Beth Terry M, Tessier DC, Thanasitthichai S, Thöne K, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Truong T, Tseng CC, Tsugane S, Ulmer HU, Ursin G, Untch M, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van der Kolk L, van der Luijt RB, Vincent D, Vollenweider J, Waisfisz Q, Wang-Gohrke S, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yamaji T, Yang XR, Har Yip C, Yoo KY, Yu JC, Zheng W, Zheng Y, Zhu B, Ziogas A, Ziv E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani SR, Antoniou AC, Droit A, Andrulis IL, Amos CI, Couch FJ, Pharoah PDP, Chang-Claude J, Hall P, Hunter DJ, Milne RL, García-Closas M, Schmidt MK, Chanock SJ, Dunning AM, Edwards SL, Bader GD, Chenevix-Trench G, Simard J, Kraft P, Easton DF
(2017) Nature 551: 92-94
MeSH Terms: Asia, Asian Continental Ancestry Group, Binding Sites, Breast Neoplasms, Computer Simulation, Europe, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Risk Assessment, Transcription Factors
Show Abstract · Added April 3, 2018
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
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17 MeSH Terms
Integrative genetic analysis suggests that skin color modifies the genetic architecture of melanoma.
Hulur I, Skol AD, Gamazon ER, Cox NJ, Onel K
(2017) PLoS One 12: e0185730
MeSH Terms: European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Melanoma, Models, Genetic, Polymorphism, Single Nucleotide, Skin Neoplasms, Skin Pigmentation
Show Abstract · Added October 27, 2017
Melanoma is the deadliest form of skin cancer and presents a significant health care burden in many countries. In addition to ultraviolet radiation in sunlight, the main causal factor for melanoma, genetic factors also play an important role in melanoma susceptibility. Although genome-wide association studies have identified many single nucleotide polymorphisms associated with melanoma, little is known about the proportion of disease risk attributable to these loci and their distribution throughout the genome. Here, we investigated the genetic architecture of melanoma in 1,888 cases and 990 controls of European non-Hispanic ancestry. We estimated the overall narrow-sense heritability of melanoma to be 0.18 (P < 0.03), indicating that genetics contributes significantly to the risk of sporadically-occurring melanoma. We then demonstrated that only a small proportion of this risk is attributable to known risk variants, suggesting that much remains unknown of the role of genetics in melanoma. To investigate further the genetic architecture of melanoma, we partitioned the heritability by chromosome, minor allele frequency, and functional annotations. We showed that common genetic variation contributes significantly to melanoma risk, with a risk model defined by a handful of genomic regions rather than many risk loci distributed throughout the genome. We also demonstrated that variants affecting gene expression in skin account for a significant proportion of the heritability, and are enriched among melanoma risk loci. Finally, by incorporating skin color into our analyses, we observed both a shift in significance for melanoma-associated loci and an enrichment of expression quantitative trait loci among melanoma susceptibility variants. These findings suggest that skin color may be an important modifier of melanoma risk. We speculate that incorporating skin color and other non-genetic factors into genetic studies may allow for an improved understanding of melanoma susceptibility and guide future investigations to identify melanoma risk genes.
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13 MeSH Terms
Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.
Weng LC, Lunetta KL, Müller-Nurasyid M, Smith AV, Thériault S, Weeke PE, Barnard J, Bis JC, Lyytikäinen LP, Kleber ME, Martinsson A, Lin HJ, Rienstra M, Trompet S, Krijthe BP, Dörr M, Klarin D, Chasman DI, Sinner MF, Waldenberger M, Launer LJ, Harris TB, Soliman EZ, Alonso A, Paré G, Teixeira PL, Denny JC, Shoemaker MB, Van Wagoner DR, Smith JD, Psaty BM, Sotoodehnia N, Taylor KD, Kähönen M, Nikus K, Delgado GE, Melander O, Engström G, Yao J, Guo X, Christophersen IE, Ellinor PT, Geelhoed B, Verweij N, Macfarlane P, Ford I, Heeringa J, Franco OH, Uitterlinden AG, Völker U, Teumer A, Rose LM, Kääb S, Gudnason V, Arking DE, Conen D, Roden DM, Chung MK, Heckbert SR, Benjamin EJ, Lehtimäki T, März W, Smith JG, Rotter JI, van der Harst P, Jukema JW, Stricker BH, Felix SB, Albert CM, Lubitz SA
(2017) Sci Rep 7: 11303
MeSH Terms: Age Factors, Aged, Atrial Fibrillation, Body Mass Index, Chromosomes, Human, Pair 4, Epistasis, Genetic, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Reproducibility of Results, Risk Factors, Sex Characteristics
Show Abstract · Added March 14, 2018
It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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19 MeSH Terms
A multi-stage genome-wide association study of uterine fibroids in African Americans.
Hellwege JN, Jeff JM, Wise LA, Gallagher CS, Wellons M, Hartmann KE, Jones SF, Torstenson ES, Dickinson S, Ruiz-Narváez EA, Rohland N, Allen A, Reich D, Tandon A, Pasaniuc B, Mancuso N, Im HK, Hinds DA, Palmer JR, Rosenberg L, Denny JC, Roden DM, Stewart EA, Morton CC, Kenny EE, Edwards TL, Velez Edwards DR
(2017) Hum Genet 136: 1363-1373
MeSH Terms: Adult, African Americans, Alleles, Cell Adhesion Molecules, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors, Humans, Leiomyoma, Middle Aged, Neoplasm Proteins, Risk Factors, Uterine Neoplasms
Show Abstract · Added March 14, 2018
Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women's Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16-1.30), p value = 7.82 × 10). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids.
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16 MeSH Terms
Evidence of selection on splicing-associated loci in human populations and relevance to disease loci mapping.
Gamazon ER, Konkashbaev A, Derks EM, Cox NJ, Lee Y
(2017) Sci Rep 7: 5980
MeSH Terms: Chromosome Mapping, Disease, Genetic Loci, Genetics, Population, Genome-Wide Association Study, Humans, Introns, Nucleotide Motifs, Polymorphism, Single Nucleotide, RNA Splicing, Selection, Genetic
Show Abstract · Added October 27, 2017
We performed a whole-genome scan of genetic variants in splicing regulatory elements (SREs) and evaluated the extent to which natural selection has shaped extant patterns of variation in SREs. We investigated the degree of differentiation of single nucleotide polymorphisms (SNPs) in SREs among human populations and applied long-range haplotype- and multilocus allelic differentiation-based methods to detect selection signatures. We describe an approach, sampling a large number of loci across the genome from functional classes and using the consensus from multiple tests, for identifying candidates for selection signals. SRE SNPs in various SNP functional classes show different patterns of population differentiation compared with their non-SRE counterparts. Intronic regions display a greater enrichment for extreme population differentiation among the potentially tissue-dependent transcript ratio quantitative trait loci (trQTLs) than SRE SNPs in general and includ outlier trQTLs for cross-population composite likelihood ratio, suggesting that incorporation of context annotation for regulatory variation may lead to improved detection of signature of selection on these loci. The proportion of extremely rare SNPs disrupting SREs is significantly higher in European than in African samples. The approach developed here will be broadly useful for studies of function and disease-associated variation in the human genome.
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11 MeSH Terms