Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche

School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, United States of America.
PLoS Genetics (Impact Factor: 8.17). 03/2009; 5(3):e1000420. DOI: 10.1371/journal.pgen.1000420
Source: PubMed

ABSTRACT For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects--all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09 x 10(-3) and 4.37 x 10(-3), respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19 x 10(-5) and 1.02 x 10(-4), respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of relatively low numbers of sires in cattle breeding programs, particularly on those for carcass and weight traits in Nellore beef cattle (Bos indicus) in Brazil, has always raised concerns about inbreeding, which affects conservation of genetic resources and sustainability of this breed. Here, we investigated the distribution of autozygosity levels based on runs of homozygosity (ROH) in a sample of 1,278 Nellore cows, genotyped for over 777,000 SNPs. We found ROH segments larger than 10 Mb in over 70% of the samples, representing signatures most likely related to the recent massive use of few sires. However, the average genome coverage by ROH (>1 Mb) was lower than previously reported for other cattle breeds (4.58%). In spite of 99.98% of the SNPs being included within a ROH in at least one individual, only 19.37% of the markers were encompassed by common ROH, suggesting that the ongoing selection for weight, carcass and reproductive traits in this population is too recent to have produced selection signatures in the form of ROH. Three short-range highly prevalent ROH autosomal hotspots (occurring in over 50% of the samples) were observed, indicating candidate regions most likely under selection since before the foundation of Brazilian Nellore cattle. The putative signatures of selection on chromosomes 4, 7, and 12 may be involved in resistance to infectious diseases and fertility, and should be subject of future investigation.
    Frontiers in Genetics 01/2015; 6. DOI:10.3389/fgene.2015.00005
  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine if binge ethanol consumption before ovulation affects oocyte quality, gene expression, and subsequent embryo development. Binge levels of ethanol were given twice weekly for 6 months, followed by a standard in vitro fertilization cycle and subsequent natural mating. National primate research center. Adult female rhesus monkeys. Binge levels of ethanol, given twice weekly for 6 months before a standard in vitro fertilization cycle with or without embryo culture. With in vivo development, ethanol treatment continued until pregnancy was identified. Oocyte and cumulus/granulosa cell gene expression, embryo development to blastocyst, and pregnancy rate. Embryo development in vitro was reduced; changes were found in oocyte and cumulus cell gene expression; and spontaneous abortion during very early gestation increased. This study provides evidence that binge drinking can affect the developmental potential of oocytes even after alcohol consumption has ceased. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
    Fertility and Sterility 12/2014; DOI:10.1016/j.fertnstert.2014.10.051 · 4.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human pygmy populations inhabit different regions of the world, from Africa to Melanesia. In Asia, short-statured populations are often referred to as "negritos." Their short stature has been interpreted as a consequence of thermoregulatory, nutritional, and/or locomotory adaptations to life in tropical forests. A more recent hypothesis proposes that their stature is the outcome of a life history trade-off in high-mortality environments, where early reproduction is favored and, consequently, early sexual maturation and early growth cessation have coevolved. Some serological evidence of deficiencies in the growth hormone/insulin-like growth factor axis have been previously associated with pygmies' short stature. Using genome-wide single-nucleotide polymorphism genotype data, we first tested whether different negrito groups living in the Philippines and Papua New Guinea are closely related and then investigated genomic signals of recent positive selection in African, Asian, and Papuan pygmy populations. We found that negritos in the Philippines and Papua New Guinea are genetically more similar to their nonpygmy neighbors than to one another and have experienced positive selection at different genes. These results indicate that geographically distant pygmy groups are likely to have evolved their short stature independently. We also found that selection on common height variants is unlikely to explain their short stature and that different genes associated with growth, thyroid function, and sexual development are under selection in different pygmy groups.
    Human Biology 12/2013; 85(1-3):251-84. DOI:10.3378/027.085.0313 · 1.52 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014