title: Identification of a novel percent mammographic density locus at 12q24.
abstract: Percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer and has a heritable component that remains largely unidentified. We performed a three-stage genome-wide association study (GWAS) of percent mammographic density to identify novel genetic loci associated with this trait. In stage 1, we combined three GWASs of percent density comprised of 1241 women from studies at the Mayo Clinic and identified the top 48 loci (99 single nucleotide polymorphisms). We attempted replication of these loci in 7018 women from seven additional studies (stage 2). The meta-analysis of stage 1 and 2 data identified a novel locus, rs1265507 on 12q24, associated with percent density, adjusting for age and BMI (P = 4.43 × 10(-8)). We refined the 12q24 locus with 459 additional variants (stage 3) in a combined analysis of all three stages (n = 10 377) and confirmed that rs1265507 has the strongest association in the 12q24 region (P = 1.03 × 10(-8)). Rs1265507 is located between the genes TBX5 and TBX3, which are members of the phylogenetically conserved T-box gene family and encode transcription factors involved in developmental regulation. Understanding the mechanism underlying this association will provide insight into the genetics of breast tissue composition.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Charlton 6-239, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Stevens
authors.forename: Sara
authors.initials: S
authors.lastname: Lindstrom
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Scott
authors.forename: Deborah
authors.initials: D
authors.lastname: Thompson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.forename: Xianshu
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authors.lastname: Wang
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authors.lastname: Wang
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authors.lastname: Atkinson
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authors.initials: DN
authors.lastname: Rider
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authors.initials: JE
authors.lastname: Eckel-Passow
authors.forename: Jajini S
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authors.lastname: Varghese
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authors.lastname: Audley
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authors.lastname: Brown
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authors.lastname: Wareham
authors.forename: Jingmei
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authors.forename: Per
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authors.lastname: Hall
authors.forename: Jianjun
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authors.forename: Kamila
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authors.lastname: Czene
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authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Zachary
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authors.lastname: Fredericksen
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
authors.forename: Adam M
authors.initials: AM
authors.lastname: Lee
authors.forename: John A
authors.initials: JA
authors.lastname: Heit
authors.forename: Mariza
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authors.lastname: DeAndrade
authors.forename: Ellen L
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authors.lastname: Goode
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authors.lastname: Vierkant
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Sebastian M
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authors.lastname: Armasu
authors.forename: Richard
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authors.lastname: Weinshilboum
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Anthony
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authors.lastname: Batzler
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Norman F
authors.initials: NF
authors.lastname: Boyd
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Johanna
authors.initials: J
authors.lastname: Rommens
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Melissa C
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authors.lastname: Southey
authors.forename: Jennifer
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authors.lastname: Stone
authors.forename: Carmel
authors.initials: C
authors.lastname: Apicella
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: Aditi
authors.initials: A
authors.lastname: Hazra
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Rulla M
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authors.lastname: Tamimi
authors.forename: Celine M
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authors.lastname: Vachon
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D042361:Mammary Glands, Human / Q000737:chemistry* / Q000528:radiation effects; D008327:Mammography; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D020825:T-Box Domain Proteins / Q000235:genetics; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C106884:TBX3 protein, human