Genome-wide association analysis identifies 20 loci that influence adult height
NATURE GENETICS
Authors: Weedon, Michael N.; Lango, Hana; Lindgren, Cecilia M.; Wallace, Chris; Evans, David M.; Mangino, Massimo; Freathy, Rachel M.; Perry, John R. B.; Stevens, Suzanne; Hall, Alistair S.; Samani, Nilesh J.; Shields, Beverly; Prokopenko, Inga; Farrall, Martin; Dominiczak, Anna; Johnson, Toby; Bergmann, Sven; Beckmann, Jacques S.; Vollenweider, Peter; Waterworth, Dawn M.; Mooser, Vincent; Palmer, Colin N. A.; Morris, Andrew D.; Ouwehand, Willem H.; Caulfield, Mark; Munroe, Patricia B.; Hattersley, Andrew T.; McCarthy, Mark I.; Frayling, Timothy M.
Abstract
Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height ( P < 5 x 10(-7), with 10 reaching P < 1 iota x 10(-10)). Combined, the 20 SNPs explain similar to 3% of height variation, with a similar to 5 cm difference between the 6.2% of people with iota 7 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling ( IHH, HHIP, PTCH1), extracellular matrix ( EFEMP1, ADAMTSL3, ACAN) and cancer ( CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.
Identification of a Preneoplastic Gene Expression Profile in Tubal Epithelium of BRCA1 Mutation Carriers
NEOPLASIA
Authors: Press, Joshua Z.; Wurz, Kaitlyn; Norquist, Barbara M.; Lee, Ming K.; Pennil, Christopher; Garcia, Rochelle; Welcsh, Piri; Goff, Barbara A.; Swisher, Elizabeth M.
Abstract
Microinvasive carcinomas and high-grade intraepithelial neoplasms are commonly discovered within the fallopian tube of BRCA1 mutation carriers at the time of risk-reducing salpingo-oophorectomy, suggesting that many BRCA1-mutated ovarian carcinomas originate in tubal epithelium. We hypothesized that changes in gene expression profiles within the histologically normal fallopian tube epithelium of BRCA1 mutation carriers would overlap with the expression profiles in BRCA1-mutated ovarian carcinomas and represent a BRCA1 preneoplastic signature. Laser capture microdissection of frozen sections was used to isolate neoplastic cells or histologically normal fallopian tube epithelium, and expression profiles were generated on Affymetrix U133 Plus 2.0 gene expression arrays. Normal-risk controls were 11 women wild type for BRCA1 and BRCA2 (WT-FT). WT-FT were compared with histologically normal fallopian tube epithelium from seven women with deleterious BRCA1 mutations who had foci of at least intraepithelial neoplasm within their fallopian tube (B1-FTocc). WT-FT samples were also compared with 12 BRCA1 ovarian carcinomas (B1-CA). The comparison of WT-FT versus B1-FTocc resulted in 152 differentially expressed probe sets, and the comparison of WT-FT versus B1-CA resulted in 4079 differentially expressed probe sets. The BRCA1 preneoplastic signature was composed of the overlap between these two lists, which included 41 concordant probe sets. Genes in the BRCA1 preneoplastic signature included several known tumor suppressor genes such as CDKN1C and EFEMP1 and several thought to be important in invasion and metastasis such as E2F3. The expression of a subset of genes was validated with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry.
COA
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