Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
23040493
TITLE
Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata.
ABSTRACT
Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scores > 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05 × 10(-8)) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention.
Copyright 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2012 Oct 5
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2012/06/29
revised 2012/08/06
accepted 2012/08/13
entrez 2012/10/09 06:00
pubmed 2012/10/09 06:00
medline 2013/03/19 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Eggert SL Eggert Stacey L SL Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Huyck KL Huyck Karen L KL
Somasundaram P Somasundaram Priya P
Kavalla R Kavalla Raghava R
Stewart EA Stewart Elizabeth A EA
Lu AT Lu Ake T AT
Painter JN Painter Jodie N JN
Montgomery GW Montgomery Grant W GW
Medland SE Medland Sarah E SE
Nyholt DR Nyholt Dale R DR
Treloar SA Treloar Susan A SA
Zondervan KT Zondervan Krina T KT
Heath AC Heath Andrew C AC
Madden PA Madden Pamela A F PA
Rose L Rose Lynda L
Buring JE Buring Julie E JE
Ridker PM Ridker Paul M PM
Chasman DI Chasman Daniel I DI
Martin NG Martin Nicholas G NG
Cantor RM Cantor Rita M RM
Morton CC Morton Cynthia C CC
INVESTIGATORS
JOURNAL
VOLUME: 91
ISSUE: 4
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2012
MONTH: Oct
DAY: 5
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
084766 Wellcome Trust United Kingdom
085235 Wellcome Trust United Kingdom
090532 Wellcome Trust United Kingdom
AA07535 NIAAA NIH HHS United States
AA07728 NIAAA NIH HHS United States
AA11998 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA14041 NIAAA NIH HHS United States
AA17688 NIAAA NIH HHS United States
CA047988 NCI NIH HHS United States
DA012854 NIDA NIH HHS United States
DA019951 NIDA NIH HHS United States
HD046226 NICHD NIH HHS United States
HD060530 NICHD NIH HHS United States
HHSN268200782096C PHS HHS United States
HL043851 NHLBI NIH HHS United States
HL69757 NHLBI NIH HHS United States
K05 AA017688 NIAAA NIH HHS United States
R01 HD060530 NICHD NIH HHS United States
U01 HL069757 NHLBI NIH HHS United States
WT085235/Z/08/Z Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Alleles
Cohort Studies
Fatty Acid Synthase, Type I genetics
Female genetics
Genetic Linkage genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study methods
Genotype methods
Humans methods
Hysterectomy methods
Leiomyoma surgery
Linkage Disequilibrium surgery
Lod Score surgery
Monocarboxylic Acid Transporters genetics
Polymorphism, Single Nucleotide genetics
RNA, Messenger genetics
Siblings genetics
Uterine Neoplasms surgery
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Monocarboxylic Acid Transporters
0 RNA, Messenger
0 SLC16A3 protein, human
EC 2.3.1.85 FASN protein, human
EC 2.3.1.85 Fatty Acid Synthase, Type I
OTHER ID's
OTHERID SOURCE
PMC3484658 NLM