Whole Genome Analysis for the Detection of Key Genes in the Polycystic Ovary Syndrome
Whole Genome Analysis for the Detection of Key Genes in the Polycystic Ovary Syndrome
Background: Infertility affects up to 15% of married couples. About half are attributable to
 female factors, among which anovulation is the leading cause. Some 5% of all women of
 reproductive age are anovulatory due to the polycystic ovarian syndrome (PCOS). PCOS causes
 also major health and cosmetic problems and significantly affects quality of life. PCOS is
 associated with cardiovascular morbidity and Type 2 diabetes mellitus, but it is unclear
 whether these are caused by the ovarian dysfunction or result from a common denominator.

 Working hypothesis and aims: Whole genome analysis of multigenerational families in which at
 least one woman is affected by PCOS may significantly reduce the numbers needed to verify the
 specific genes, involved in the causation of PCOS.

 Methods: Registration of multigenerational families and production of personal files with
 full workup for the presence of PCOS or its absence (in the women participants). Drawing of
 blood, extraction and preservation of DNA. Analysis of all informative SNPs in the genomes of
 the participants on a specific microarray chip. Statistical analysis of the results.

 Expected results: Verification of the loci and putative genes, associated with the appearance
 of PCOS.

 Importance: Elucidation of the specific genes underlying the pathology of PCOS. Probable
 implications to Medicine: Paving the way for targeted treatment of the problems, associated
 with PCOS, based on the clear knowledge of its underlying cause(s).
1. Working Hypothesis The recent trend in GWA has been the comparison of large numbers of
 DNA samples from affected individuals and large pools of unrelated individuals (Wellcome
 Trust Case Control Consortium). Whenever the control group came from family members, the
 number of patients needed to be sampled has been consistently smaller (Dempfle a et al
 2006; The Japanese Schizophrenia Sib-Pair Linkage Group 2005), due to less degrees of
 freedom in the statistical analysis (Chen WM & Abecasis GR 2007).

 2. Specific Aims

 1. What are the specific informative SNPs, associated with PCOD?

 2. What are the specific genes located in the vicinity of these SNPs, which could
 contribute to the development of the clinical syndrome? Detailed description of the
 proposed research Clinical data collection and patient recruitment Patients

 Women will be diagnosed as suffering from PCOD based on the Rotterdam criteria ():

 1. Oligo- and/or anovulation

 2. Clinical and/or biochemical signs of hyperandrogenism

 3. Polycystic ovaries, and exclusion of other aetiologies (congenital adrenal
 hyperplasias, androgen-secreting tumours, Cushing's syndrome) Routine testing of
 serum levels for the relevant sex hormones will be performed at the 3rd day of the
 menstrual cycle. Glucose and insulin levels will be measured at the fasting state.
 The individual data collection page is presented as Appendix 1.

 Controls Sisters, mothers, fathers, aunts and grandmothers of affected women will be
 asked to disclose their relevant clinical history and donate a single blood test for
 both DNA extraction and hormonal tests, which will be taken at the 3rd day of
 menstruation, where applicable.

 The population that is served by Mayanei Hayeshua hospital is characterized by a short
 generation interval, due to the mean early age at marriage and the desire to bear
 children right after marriage. This should allow the formation of genealogy trees that
 are very informative.

 Data security and terms of use of samples Recruitment of family members will be only
 through the index cases, and each participant will receive a complete explanation of
 possible personal implication of the study results to herself and family (none).
 Overall, all included women, patients and family members alike, will be notified as to
 the secrecy of the data and its use only for the declared purpose of research. They will
 also be made aware that no personal benefit or harm can be derived from this data to
 them. In addition, all participants will be informed that if in the future there will
 arise a new reason to re-analyze their samples, a specific address will be made to each
 and every one of them to obtain a new permission for this use. Upon request each
 participant will receive a full explanation of the storage system and the hierarchy of
 responsibility for the samples and data security.

 3. Compliance to the definition of a feasibility study The funds requested herein are meant
 to enable the formation of DNA bank and family trees, which in turn will serve as the
 basis for an application to receive the full funding for whole genome analysis, from
 larger funding resources. Towards this we have teamed up with the future participants of
 a worldwide consortium on this topic (letter of intention from Bart Fauser, the leading
 person of this consortium, is attached). Our most pronounced advantage within the
 consortium, is the availability of multigenerational families, members of which we treat
 in Bnei Brak.

 4. Potential Implications to Medicine and contribution of the expected outcome to society
 Paving the way for targeted treatment of the problems, associated with PCOS, based on
 the clear knowledge of its underlying cause(s).
Inclusion Criteria:

 -  A clinical and laboratory diagnosis of the polycystic ovary syndrome (cases). Female
 family members of index cases, up to a great grandmother and fathers of index cases.

 Exclusion Criteria:

 -  None.