The role of common and rare DNA sequence
variants in susceptibility to PCOS.
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Thesis
Samantha Liew
31151399
Honours in Molecular Biology 2013
Supervisors
A/Prof Scott Wilson
Endocrinology and Diabetes
Sir Charles Gairdner Hospital
Prof Bronwyn Stuckey
Endocrinology and Diabetes
Sir Charles Gairdner Hospital
A/Prof Robert Mead
Biological Sciences and Biotechnology
Murdoch University
ABSTRACT
Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women of
reproductive age, and has a strong familial component. A recent genome-wide
association study (GWAS) of PCOS in a population of Han Chinese identified three
reproducible PCOS susceptibility loci; 9q33.3 (DENND1A), 2p21 (THADA) and
2p16.3 (LHCGR). This study aims to replicate the association between PCOS and
these susceptibility loci in a population of Western Australian (WA) women. This
included 199 PCOS cases and 162 controls.
Two single nucleotide polymorphisms (SNPs) rs10818854 in DENND1A and
rs12468394 in THADA were tested for association with PCOS in a WA PCOS cohort.
These PCOS cases were defined according to the National Institute of Health (NIH)
criteria for PCOS. Statistical analyses of the data showed that these variants in
DENND1A and THADA were not associated with PCOS in the women from the
cohort of the Western Australian Genetic Database of PCOS Women (WAGDPW).
The relatively low number of participants in this study and European ancestry of the
study subjects investigated in this project could be factors relevant to the difference
in the findings. Further studies taken should be encouraged to increase sample sizes
up to 2000 PCOS subjects for adequate statistical power.
A clinical recruitment of 20 pairs of affected mothers and daughters were carried out
to expand the WA-PCOS cohort. 16 individuals responded to the invitation to
participate in the research, from which 5 mother-daughter pairs were recruited. This
recruitment forms an important foundation for future family based recruitment
programs of POS. Clinical recruitment proved to be a challenge in this study in which
methods of recruitment can be improved. DNA from individuals recruited during this
study was subsequently used in an experiment for exome sequencing (ES).
ES was performed on five individuals who had clear evidence of familial PCOS. A
possible candidate locus, rs189947178 in DENND1A was identified as potentially
relevant to the disease and further studies are recommended to be carried out to
understand the role of this SNP in association with PCOS.
A number of PCOS women with whole genome sequencing (WGS) data available
were also studied. Candidate genes; DENND1A, THADA, LHCGR data were
analysed in these 16 individuals. The presence of functional genetic mutations within
the key candidate genes in the 16 individuals were investigated. A variant, in the
vicinity of the THADA gene was highlighted by these studies. However, further
studies are required to elaborate the potential role of this DNA sequence variant in
relation to PCOS.
In conclusion, this study of Perth women of Eurpoean ancestry could not replicate the
reported association between the two loci (rs10818854 and rs12468394) and PCOS.
ES and WGS have identified a number of possible candidate genes/loci and future
tests can be carried out to validate the possibility of any association with PCOS.
Studying these genes in a larger sample sizes may contribute to further our
understanding the genetics mechanisms of PCOS.