Thesis supervisor: Prof. Maris Laan, University of Tartu
Opponent: Dr. Daniel Vaiman, Cochin Institute, INSERM, Paris Descartes University, France
Spontaneous pregnancy loss is the most common pregnancy complication. Up to 3% of fertile couples have been diagnosed with recurrent miscarriage disease (RM), defined as three or more consecutive early pregnancy losses. Although a spectrum of causes is known for RM, etiology behind approximately half of the cases remains unsolved. This thesis aimed to map the genetic determinants of unexplained RM by addressing gene-specific single nucleotide variants but also genome-wide profile of DNA copy number changes.
The fine-scale analysis of gene-specific markers focused on the human chorionic gonadotropin (hCG), the 'pregnancy hormone', essential for pregnancy establishment and maintenance. The thesis reports the complex genomic architecture and genetic diversity of the gene family encoding the β-subunit of hCG. Case-control study of genetic variants in the two most actively expressed hCGβ genes CGB5 and CGB8 in Estonia, Finland and Denmark and functional study of non-synonymous mutations within these genes identified only DNA markers with neutral or protective effect towards RM. Results indicate that preserving the hCGβ genes as functionally active is a prerequisite for early pregnancy success.
DNA copy number variants (CNVs) involve DNA rearrangements larger than 50 basepairs. Global enrichment of CNVs has previously been associated with several complex diseases, however few studies have addressed CNVs in the context of reproductive disorders. Genome-wide CNV study in RM cases revealed the impact of DNA rearrangements on genes related to maternal immune tolerance in the placenta. A novel DNA duplication on chromosome 5 was identified from the genome-wide CNV profile increasing maternal risk of RM up to 4.8 times in Estonia and Denmark. The duplication involves two genes PDZD2 and GOLPH3 with major expression in placenta and associated with early pregnancy maintenance for the first time.