Calculation and use of the Hardy-Weinberg model in association studies.
ABSTRACT Hardy-Weinberg equilibrium (HWE) is an important tool for understanding population structure. If certain assumptions are met, genotype and allele frequencies can be estimated from one generation to the next. In genetic association studies, HWE principles have been applied to detect genotyping error and disease susceptibility loci. The focus of this unit is to review the key principles and assumptions of HWE. There is a brief discussion on how the significance of HWE is tested, and a review of current applications of HWE in association studies. The applications discussed include estimating penetrance, evaluating genotyping errors, testing for population stratification, and testing for association.
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ABSTRACT: Analysis of genetic polymorphisms may help identify putative prognostic markers and determine the biological basis of variable prognosis in patients. However, in contrast to other variables commonly used in the prognostic studies, there are special considerations when studying genetic polymorphisms. For example, variable inheritance patterns (recessive, dominant, codominant, and additive genetic models) need to be explored to identify the specific genotypes associated with the outcome. In addition, several characteristics of genetic polymorphisms, such as their minor allele frequency and linkage disequilibrium among multiple polymorphisms, and the population substructure of the cohort investigated need to be accounted for in the analyses. In addition, in cancer research due to the genomic differences between the tumor and non-tumor DNA, differences in the genetic information obtained using these tissues need to be carefully assessed in prognostic studies. In this article, we review these and other considerations specific to genetic polymorphism by focusing on genetic prognostic studies in cancer.BMC Medicine 06/2013; 11(1):149. DOI:10.1186/1741-7015-11-149 · 7.28 Impact Factor
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ABSTRACT: Highlights • LHB variants do not correlate with an increased risk of PCOS • Trp28Arf/Ile35Thr LHB variant was more frequent in PCOS women with hyperandrogenemia • PCOS phenotype may be modulated by gene variants involving androgen-related pathways Introduction Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder, of multifactorial etiology, which affects 6-10% of women of reproductive age. It is considered the leading cause of anovulatory infertility, menstrual disorders and hyperandrogenism in this population. The genetic basis of PCOS is still largely unknown despite significant family clustering; determining its mode of inheritance is particularly difficult given the heterogenic presentation of the disease. Materials and Methods 130 Brazilian women, aged 14–42 years, who met the 2003 Rotterdam criteria for PCOS diagnosis, were included, and 96 healthy women constituted the control group. Presence of hirsutism was classified using the modified Ferriman-Gallwey score (F-G score) as absent (≤ 7), mild (8–14), and severe (≥ 15). Blood levels of luteinizing hormone (LH), total testosterone (TT), dehydroepiandrosterone sulphate (DHEA-S) and androstenedione were determined. The coding region of the luteinizing hormone beta-subunit (LHB) gene was amplified and sequenced. Differences in allelic and genotypic frequency distribution of each polymorphism across controls and cases were estimated by the Mantel-Haenszel chi-square or Fisher’s exact test (p < 0.05), and the probability of an association between the detection of a polymorphism and presence of a diagnosis of PCOS, by logistic regression. Result(s) Sequencing detected 8 polymorphisms in the LHB gene coding region. Two polymorphisms in linkage disequilibrium were significantly more prevalent in the presence of hyperandrogenemia: rs1800447/rs34349826 (Trp28Arg/Ile35Thr) (p = 0.02). Conclusion(s) In this series, a modulatory effect of LHB polymorphisms on hyperandrogenemia phenotype of PCOS was observed; however, this finding needs to be replicated in other populations. Abbreviations LH, luteinizing hormone; LHB, luteinizing hormone beta subunit; PCOS, Polycystic Ovary Syndrome; BMI, body mass index; TT, total testosterone; DHEA-S, dehydroepiandrosterone sulphate; IFG, impaired fasting glucose levels; F-G score, Ferriman Gallwey score; GWAS, genome-wide association study; AR, androgen receptor Keywords polycystic ovary syndrome; LHB gene; gene polymorphism; hyperandrogenemia; hirsutismGene 10/2014; 550(1):68-73. DOI:10.1016/j.gene.2014.08.017 · 2.08 Impact Factor