Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Kate Lawrenson; Siddhartha Kar; Karen McCue; Karoline Kuchenbaeker; Kyriaki Michailidou; Jonathan Tyrer; Jonathan Beesley; Susan J Ramus; Qiyuan Li; Melissa K Delgado; Janet M Lee; Kristiina Aittomäki; Irene L Andrulis; Hoda Anton-Culver; Volker Arndt; Banu K Arun; Brita Arver; Elisa V Bandera; Monica Barile; Rosa B Barkardottir; Daniel Barrowdale; Matthias W Beckmann; Javier Benitez; Andrew Berchuck; Maria Bisogna; Line Bjorge; Carl Blomqvist; William Blot; Natalia Bogdanova; Anders Bojesen; Stig E Bojesen; Manjeet K Bolla; Bernardo Bonanni; Anne-Lise Børresen-Dale; Hiltrud Brauch; Paul Brennan; Hermann Brenner; Fiona Bruinsma; Joan Brunet; Shaik Ahmad Buhari; Barbara Burwinkel; Ralf Butzow; Saundra S Buys; Qiuyin Cai; Trinidad Caldes; Ian Campbell; Rikki Canniotto; Jenny Chang-Claude; Jocelyne Chiquette; Ji-Yeob Choi; Kathleen B. M Claes; Linda S Cook; Angela Cox; Daniel W Cramer; Simon S Cross; Cezary Cybulski; Kamila Czene; Mary B Daly; Francesca Damiola; Agnieszka Dansonka-Mieszkowska; Hatef Darabi; Joe Dennis; Peter Devilee; Orland Diez; Jennifer A Doherty; Susan M Domchek; Cecilia M Dorfling; Thilo Dörk; Martine Dumont; Hans Ehrencrona; Bent Ejlertsen; Steve Ellis; Christoph Engel; Eunjung Lee; D. Gareth Evans; Peter A Fasching; Lidia Feliubadalo; Jonine Figueroa; Dieter Flesch-Janys; Henrik Flyger; Olivia Fletcher; Lenka Foretova; Florentia Fostira; William D Foulkes; Brooke L Fridley; Eitan Friedman; Debra Frost; Gaetana Gambino; Patricia A Ganz; Judy Garber; Montserrat García-Closas; Aleksandra Gentry-Maharaj; Maya Ghoussaini; Graham G Giles; Rosalind Glasspool; Andrew K Godwin; Mark S Goldberg; David E Goldgar; Anna González-Neira; Ellen L Goode; Marc T Goodman; Mark H Greene; Jacek Gronwald; Pascal Guénel; Christopher A Haiman; Per Hall; Emily Hallberg; Ute Hamann; Thomas V. O Hansen; Patricia A Harrington; Mikael Hartman; Norhashimah Hassan; Sue Healey; Florian Heitz; Josef Herzog; Estrid Høgdall; Claus K Høgdall; Frans B. L Hogervorst; Peter J Hulick; Antoinette Hollestelle; Tomasz Huzarski; John L Hopper; Evgeny N Imyanitov; Claudine Isaacs; Hidemi Ito; Anna Jakubowska; Ramunas Janavicius; Allan Jensen; Esther M John; Nichola Johnson; Maria Kabisch; Daehee Kang; Miroslav Kapuscinski; Beth Y Karlan; Sofia Khan; Lambertus A Kiemeney; Susanne Kruger Kjaer; Julia A Knight; Irene Konstantopoulou; Veli-Matti Kosma; Vessela Kristensen; Jolanta Kupryjanczyk; Ava Kwong; Miguel de la Hoya; Yael Laitman; Diether Lambrechts; Nhu Le; Kim De Leeneer; Jenny Lester; Douglas A Levine; Jingmei Li; Annika Lindblom; Jirong Long; Artitaya Lophatananon; Jennifer T Loud; Karen Lu; Jan Lubinski; Arto Mannermaa; Siranoush Manoukian; Loic Le Marchand; Sara Margolin; Frederik Marme; Leon F. A. G Massuger; Keitaro Matsuo; Sylvie Mazoyer; Lesley McGuffog; Catriona McLean; Iain McNeish; Alfons Meindl; Usha Menon; Arjen R Mensenkamp; Roger L Milne; Marco Montagna; Kirsten B Moysich; Kenneth Muir; Anna Marie Mulligan; Katherine L Nathanson; Roberta B Ness; Susan L Neuhausen; Heli Nevanlinna; Silje Nord; Robert L Nussbaum; Kunle Odunsi; Kenneth Offit; Edith Olah; Olufunmilayo I Olopade; Janet E Olson; Curtis Olswold; David O'Malley; Irene Orlow; Nick Orr; Ana Osorio; Sue Kyung Park; Celeste L Pearce; Tanja Pejovic; Paolo Peterlongo; Georg Pfeiler; Catherine M Phelan; Elizabeth M Poole; Katri Pylkäs; Paolo Radice; Johanna Rantala; Muhammad Usman Rashid; Gad Rennert; Valerie Rhenius; Kerstin Rhiem; Harvey A Risch; Gus Rodriguez; Mary Anne Rossing; Anja Rudolph; Helga B Salvesen; Suleeporn Sangrajrang; Elinor J Sawyer; Joellen M Schildkraut; Marjanka K Schmidt; Rita K Schmutzler; Thomas A Sellers; Caroline Seynaeve; Mitul Shah; Chen-Yang Shen; Xiao-Ou Shu; Weiva Sieh; Christian F Singer; Olga M Sinilnikova; Susan Slager; Honglin Song; Penny Soucy; Melissa C Southey; Marie Stenmark-Askmalm; Dominique Stoppa-Lyonnet; Christian Sutter; Anthony Swerdlow; Sandrine Tchatchou; Manuel R Teixeira; Soo H Teo; Kathryn L Terry; Mary Beth Terry; Mads Thomassen; Maria Grazia Tibiletti; Laima Tihomirova; Silvia Tognazzo; Amanda Ewart Toland; Ian Tomlinson; Diana Torres; Thérèse Truong; Chiu-chen Tseng; Nadine Tung; Shelley S Tworoger; Celine Vachon; Ans M. W van den Ouweland; Helena C van Doorn; Elizabeth J van Rensburg; Laura J Van't Veer; Adriaan Vanderstichele; Ignace Vergote; Joseph Vijai; Qin Wang; Shan Wang-Gohrke; Jeffrey N Weitzel; Nicolas Wentzensen; Alice S Whittemore; Hans Wildiers; Robert Winqvist; Anna H Wu; Drakoulis Yannoukakos; Sook-Yee Yoon; Jyh-Cherng Yu; Wei Zheng; Ying Zheng; Kum Kum Khanna; Jacques Simard; Alvaro N Monteiro; Juliet D French; Fergus J Couch; Matthew L Freedman; Douglas F Easton; Alison M Dunning; KConFab Investigators; Paul D Pharoah; Stacey L Edwards; Georgia Chenevix-Trench; Antonis C Antoniou; Simon A Gayther

doi:10.1038/ncomms12675

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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Journal article

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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J Ramus, Qiyuan Li, Melissa K Delgado, …

Nature communications, Vol.7(1), pp.12675-12675

09/07/2016

DOI: https://doi.org/10.1038/ncomms12675

PMCID: PMC5023955

PMID: 27601076

Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC ( P =9.2 × 10 −20 ), ER-negative BC ( P =1.1 × 10 −13 ), BRCA1 -associated BC ( P =7.7 × 10 −16 ) and triple negative BC ( P -diff=2 × 10 −5 ). Genotype-gene expression associations are identified for candidate target genes ANKLE1 ( P =2 × 10 −3 ) and ABHD8 ( P <2 × 10 −3 ). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8 , and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk. A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

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Title: Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus
Creators: Kate Lawrenson - , Los Angeles
Siddhartha Kar - , Cambridge CB1 8RN
Karen McCue - , Brisbane, Queensland 4029
Karoline Kuchenbaeker - , Cambridge CB1 8RN
Kyriaki Michailidou - , Cambridge CB1 8RN
Jonathan Tyrer - , Cambridge CB1 8RN
Jonathan Beesley - , Brisbane, Queensland 4029
Susan J Ramus - , Los Angeles
Qiyuan Li - , Xiamen 361102
Melissa K Delgado - , Los Angeles
Janet M Lee - , Los Angeles
Kristiina Aittomäki - , Helsinki 00029 HUS
Irene L Andrulis - , Toronto, Ontario M5G 1X5
Hoda Anton-Culver - , Irvine, California 92697
Volker Arndt - , Heidelberg, 69120
Banu K Arun - , Houston, Texas 77030
Brita Arver - , Stockholm 171 77
Elisa V Bandera - , New Brunswick, New Jersey 08903
Monica Barile - , Milan 20141
Rosa B Barkardottir - , Reykjavik 600169-2039
Daniel Barrowdale - , Cambridge CB1 8RN
Matthias W Beckmann - , Erlangen 91054
Javier Benitez - , Madrid E-28029
Andrew Berchuck - , Durham, North Carolina 27710
Maria Bisogna - , New York 10065
Line Bjorge - , 5021 Bergen
Carl Blomqvist - , Helsinki FIN-00029
William Blot - , Nashville, Tennessee 37203
Natalia Bogdanova - , Hannover D-30625
Anders Bojesen - , Vejle 7100
Stig E Bojesen - , Copenhagen 2200
Manjeet K Bolla - , Cambridge CB1 8RN
Bernardo Bonanni - , Milan 20141
Anne-Lise Børresen-Dale - , Oslo N-0310
Hiltrud Brauch - , Stuttgart D-70376
Paul Brennan - , Lyon 69008
Hermann Brenner - , Heidelberg, 69120
Fiona Bruinsma - , Melbourne, Victoria 3004
Joan Brunet - , Girona 08908
Shaik Ahmad Buhari - , Singapore 119077
Barbara Burwinkel - , Heidelberg 69120
Ralf Butzow - , Helsinki 00029 HUS
Saundra S Buys - , Salt Lake City, Utah 84112
Qiuyin Cai - , Nashville, Tennessee 37203
Trinidad Caldes - , Madrid 28040
Ian Campbell - , Melbourne, Victoria 3002
Rikki Canniotto - , Elm and Carlton Streets, Buffalo 14263, New York
Jenny Chang-Claude - , Heidelberg 69121
Jocelyne Chiquette - , Québec City, Québec G1J 1Z4
Ji-Yeob Choi - , Seoul 08826
Kathleen B. M Claes - , Ghent 9000
Linda S Cook - , Albuquerque, New Mexico 87131
Angela Cox - , Sheffield S10 2TN
Daniel W Cramer - , Boston, Massachusetts 02115
Simon S Cross - , Sheffield S10 2TN
Cezary Cybulski - , Szczecin 70-115
Kamila Czene - , Stockholm SE-171 77
Mary B Daly - , Philadelphia, Pennsylvania 19111
Francesca Damiola - , Lyon 69373
Agnieszka Dansonka-Mieszkowska - , Warsaw 44-101
Hatef Darabi - , Stockholm SE-171 77
Joe Dennis - , Cambridge CB1 8RN
Peter Devilee - , Leiden 2333
Orland Diez - , Barcelona 08035
Jennifer A Doherty - , Lebanon, New Hampshire 03755
Susan M Domchek - , Philadelphia, Pennsylvania 19104
Cecilia M Dorfling - , Pretoria 0083
Thilo Dörk - , Hannover D-30625
Martine Dumont - , Québec City, Québec G1V 4G2
Hans Ehrencrona - , Uppsala 751 05
Bent Ejlertsen - , 2100 Copenhagen
Steve Ellis - , Cambridge CB1 8RN
Christoph Engel - , 04107 Leipzig
Eunjung Lee - , Los Angeles
D. Gareth Evans - , Manchester M13 9PL
Peter A Fasching - , Erlangen 91054
Lidia Feliubadalo - , Barcelona 08908
Jonine Figueroa - , Rockville, Maryland 20892
Dieter Flesch-Janys - , Hamburg 20246
Henrik Flyger - , 2730 Herlev
Olivia Fletcher - , London SW3 6JB
Lenka Foretova - , 625 00 Brno
Florentia Fostira - , Athens 153 10
William D Foulkes - , Montreal, Quebec H2W 1S6
Brooke L Fridley - , Kansas City, Kansas 66160
Eitan Friedman - , Tel-Hashomer 52621
Debra Frost - , Cambridge CB1 8RN
Gaetana Gambino - , Pisa 56126
Patricia A Ganz - , Los Angeles, California 90024
Judy Garber - , Boston, Massachusetts 02215
Montserrat García-Closas - , Rockville, Maryland 20892
Aleksandra Gentry-Maharaj - , London WC1E 6AU
Maya Ghoussaini - , Cambridge CB1 8RN
Graham G Giles - , Melbourne, Victoria 3004
Rosalind Glasspool - , Glasgow G12 0YN
Andrew K Godwin - , Kansas City, Kansas 66160
Mark S Goldberg - , Montreal, Québec H3A 1A1
David E Goldgar - , Salt Lake City, Utah 84132
Anna González-Neira - , Madrid E-28029
Ellen L Goode - , Rochester, Minnesota 55902
Marc T Goodman - , Los Angeles, California 90048
Mark H Greene - , Rockville, Maryland 20892
Jacek Gronwald - , 70-204 Szczecin
Pascal Guénel - , 94805 Villejuif
Christopher A Haiman - , Los Angeles
Per Hall - , Stockholm SE-171 77
Emily Hallberg - , Rochester, Minnesota 55902
Ute Hamann - , Heidelberg 69120
Thomas V. O Hansen - , 2100 Copenhagen
Patricia A Harrington - , Cambridge CB1 8RN
Mikael Hartman - , Singapore 119077
Norhashimah Hassan - , 50603 Kuala Lumpur
Sue Healey - , Brisbane, Queensland 4029
Florian Heitz - , 45136 Essen
Josef Herzog - , Duarte California 91010
Estrid Høgdall - , 2730 Copenhagen
Claus K Høgdall - , 2100 Copenhagen
Frans B. L Hogervorst - , 1006 Amsterdam
Peter J Hulick - , Evanston, Illinois, 60201
Antoinette Hollestelle - , 3015 Rotterdam
Tomasz Huzarski - , Szczecin 70-115
John L Hopper - , Melbourne, Victoria 3010
Evgeny N Imyanitov - , St Petersburg 197758
Claudine Isaacs - , Washington District of Columbia 20057
Hidemi Ito - , Aichi 464-8681
Anna Jakubowska - , Szczecin 70-115
Ramunas Janavicius - , LT-01102 Vilnius
Allan Jensen - , 2100 Copenhagen
Esther M John - , Fremont, California 94538
Nichola Johnson - , London SW3 6JB
Maria Kabisch - , Heidelberg 69120
Daehee Kang - , Seoul 08826
Miroslav Kapuscinski - , Melbourne, Victoria 3010
Beth Y Karlan - , Los Angeles, California 90048
Sofia Khan - , Helsinki 00029 HUS
Lambertus A Kiemeney - , 6500 Nijmegen
Susanne Kruger Kjaer - , DK-2100 Copenhagen
Julia A Knight - , Toronto, Ontario M5G 1X5
Irene Konstantopoulou - , Athens 153 10
Veli-Matti Kosma - , 70210 Kuopio
Vessela Kristensen - , Oslo N-0310
Jolanta Kupryjanczyk - , Warsaw 44-101
Ava Kwong - , Hong Kong
Miguel de la Hoya - , Madrid 28040
Yael Laitman - , Tel-Hashomer 52621
Diether Lambrechts - , 3000 Leuven
Nhu Le - , Los Angeles
Kim De Leeneer - , Ghent 9000
Jenny Lester - , Los Angeles, California 90048
Douglas A Levine - , New York 10065
Jingmei Li - , Stockholm SE-171 77
Annika Lindblom - , SE-171 77 Stockholm
Jirong Long - , Nashville, Tennessee 37203
Artitaya Lophatananon - , Coventry CV4 7AL
Jennifer T Loud - , Rockville, Maryland 20892
Karen Lu - , Houston, Texas 77030
Jan Lubinski - , Szczecin 70-115
Arto Mannermaa - , 70210 Kuopio
Siranoush Manoukian - , 20133 Milan
Loic Le Marchand - , Honolulu, Hawaii 96813
Sara Margolin - , SE-171 77 Stockholm
Frederik Marme - , Heidelberg 69120
Leon F. A. G Massuger - , 6500 Nijmegen
Keitaro Matsuo - , Fukuoka 812-8582
Sylvie Mazoyer - , Lyon 69373
Lesley McGuffog - , Cambridge CB1 8RN
Catriona McLean - , Melbourne, Victoria 3004
Iain McNeish - , Glasgow G61 1BD
Alfons Meindl - , 81675 Munich
Usha Menon - , London WC1E 6AU
Arjen R Mensenkamp - , 6500 Nijmegen
Roger L Milne - , Melbourne, Victoria 3004
Marco Montagna - , 35128 Padua
Kirsten B Moysich - , Buffalo, New York 14263
Kenneth Muir - , Coventry CV4 7AL
Anna Marie Mulligan - , Toronto, Ontario M5G 1L7
Katherine L Nathanson - , Philadelphia, Pennsylvania 19104
Roberta B Ness - , Houston, Texas 77030
Susan L Neuhausen - , Duarte, California 91010
Heli Nevanlinna - , Helsinki 00029 HUS
Silje Nord - , Oslo N-0310
Robert L Nussbaum - , San Francisco, California 94143
Kunle Odunsi - , Buffalo, New York 14263
Kenneth Offit - , New York 10065
Edith Olah - , 1122 Budapest
Olufunmilayo I Olopade - , Chicago, Illinois 60637
Janet E Olson - , Rochester, Minnesota 55902
Curtis Olswold - , Rochester, Minnesota 55902
David O'Malley - , Columbus, Ohio 43210
Irene Orlow - , New York 10017
Nick Orr - , London SW3 6JB
Ana Osorio - , 28019 Madrid
Sue Kyung Park - , Seoul 03080
Celeste L Pearce - , Los Angeles
Tanja Pejovic - , Portland, Oregon 97239
Paolo Peterlongo - , 16 20139 Milan
Georg Pfeiler - , 1090 Vienna
Catherine M Phelan - , Tampa, Florida 33606
Elizabeth M Poole - , Boston, Massachusetts 02115
Katri Pylkäs - , FI-90014 Oulu
Paolo Radice - , 20133 Milan
Johanna Rantala - , 171 76 Stockholm
Muhammad Usman Rashid - , Heidelberg 69120
Gad Rennert - , Haifa 34362
Valerie Rhenius - , Cambridge CB1 8RN
Kerstin Rhiem - , 50931 Cologne
Harvey A Risch - , New Haven, Connecticut 06510
Gus Rodriguez - , Evanston, Illinois 60201
Mary Anne Rossing - , Seattle, Washington 98109
Anja Rudolph - , Heidelberg 69121
Helga B Salvesen - , 5021 Bergen
Suleeporn Sangrajrang - , Bangkok 10400
Elinor J Sawyer - , London SE1 9RT
Joellen M Schildkraut - , Durham, North Carolina 27710
Marjanka K Schmidt - , 1066 CX Amsterdam
Rita K Schmutzler - , 50676 Cologne
Thomas A Sellers - , Tampa, Florida 33606
Caroline Seynaeve - , 3015 Rotterdam
Mitul Shah - , Cambridge CB1 8RN
Chen-Yang Shen - , Taipei 115
Xiao-Ou Shu - , Nashville, Tennessee 37203
Weiva Sieh - , Stanford California 94305
Christian F Singer - , 1090 Vienna
Olga M Sinilnikova - , Lyon 69008
Susan Slager - , Rochester, Minnesota 55902
Honglin Song - , Cambridge CB1 8RN
Penny Soucy - , Québec City, Québec G1V 4G2
Melissa C Southey - , Parkville, Victoria 3010
Marie Stenmark-Askmalm - , Lund 221 00
Dominique Stoppa-Lyonnet - , 75248 Paris
Christian Sutter - , 69120 Heidelberg
Anthony Swerdlow - , London SW7 3RP
Sandrine Tchatchou - , Toronto, Ontario M5G 1X5
Manuel R Teixeira - , Porto 4200-072
Soo H Teo - , 50603 Kuala Lumpur
Kathryn L Terry - , Boston, Massachusetts 02115
Mary Beth Terry - , New York 10027
Mads Thomassen - , 5000 Odense C
Maria Grazia Tibiletti - , 21100 Varese
Laima Tihomirova - , Riga LV-1067
Silvia Tognazzo - , 64 - 35128 Padua
Amanda Ewart Toland - , Columbus, Ohio 43210
Ian Tomlinson - , Oxford OX3 7BN
Diana Torres - , Heidelberg 69120
Thérèse Truong - , 94805 Villejuif
Chiu-chen Tseng - , Los Angeles
Nadine Tung - , Boston, Massachusetts 02215
Shelley S Tworoger - , Boston, Massachusetts 02115
Celine Vachon - , Rochester, Minnesota 55902
Ans M. W van den Ouweland - , 3015 CE Rotterdam
Helena C van Doorn - , 3015 CE Rotterdam
Elizabeth J van Rensburg - , Pretoria 0083
Laura J Van't Veer - , 1066 CX Amsterdam
Adriaan Vanderstichele - , B-3000 Leuven
Ignace Vergote - , B-3000 Leuven
Joseph Vijai - , New York 10065
Qin Wang - , Cambridge CB1 8RN
Shan Wang-Gohrke - University Hospital Ulm, 89069 Ulm
Jeffrey N Weitzel - , Duarte California 91010
Nicolas Wentzensen - , Bethesda Maryland 20892
Alice S Whittemore - , Stanford California 94305
Hans Wildiers - , B-3000 Leuven
Robert Winqvist - , FI-90014 Oulu
Anna H Wu - , Los Angeles
Drakoulis Yannoukakos - , Athens 153 10
Sook-Yee Yoon - , 47500 Subang Jaya
Jyh-Cherng Yu - , Taipei, 114
Wei Zheng - , Nashville, Tennessee 37203
Ying Zheng - , Shanghai
Kum Kum Khanna - , Brisbane, Queensland 4029
Jacques Simard - , Québec City, Québec G1V 4G2
Alvaro N Monteiro - , Tampa, Florida 33612
Juliet D French - , Brisbane, Queensland 4029
Fergus J Couch - , Rochester, Minnesota 55902
Matthew L Freedman - , Boston, Massachusetts 02215
Douglas F Easton - , Cambridge CB1 8RN
Alison M Dunning - , Cambridge CB1 8RN
KConFab Investigators
Paul D Pharoah - , Cambridge CB1 8RN
Stacey L Edwards - , Brisbane, Queensland 4029
Georgia Chenevix-Trench - , Brisbane, Queensland 4029
Antonis C Antoniou - , Cambridge CB1 8RN
Simon A Gayther - , Los Angeles
Publication Details: Nature communications, Vol.7(1), pp.12675-12675
Date published: 09/07/2016
Publisher: Nature Publishing Group
Academic Unit: Cancer Epidemiology and Health Outcomes
Language: English
Resource Type: Journal article
Identifiers: 991031666215304646