Endocrine Abstracts

Premature ovarian failure (POF) is defined as cessation of menstruation before the expected age of menopause. The disorder is considerable heterogeneous with a wide spectrum of causes- genetic, autoimmune, metabolic, infectious, and iatrogenic. However, etiology remains to be elucidated in most cases.

Chromosomal abnormalities have long been recognized as frequent causes of POF. However, few large cohorts have been studied. Ethnic background is usually not well characterized. We investigated 472 Chinese females with POF to determine the prevalence of cytogenetic anomalies in this ethnic group.

Chromosomal abnormalities were detected in 11.2% (53/472). 94.3% involved the X chromosome; 1 involved autosomes (t(13q;14q)), and 2 were 46,XY and 45,X/46,XY. We detected 15 X terminal deletions; 8 isochromosomes; 1 ring X and 1 inv X; 1 non-mosaic isodicentric, and 1 complex X arrangement. Eight X-autosome translocations were detected. Aneuploidy was found in 15 cases. Our result confirms a major role for X chromosome abnormalities in POF, highlighting the importance of routinely assessing for chromosomal abnormalities.

We sought to identify additional genetic loci associated with POF by performing the first large-scale GWAS. GWAS using Affymetrix SNP 6.0 chip was conducted in an initial discovery set of 391 Chinese POF patients, compared to 895 unrelated Chinese female controls. A replication study was then performed in an independent set of 400 cases and 800 controls. Suggestive significant associations were observed at 8q22.3. Replication of eight SNPs was confirmed. No specific candidate gene was found in the immediate region of 8q22.3. This GWAS, involving by far the largest sample of POF cases accumulated to date, revealed heretofore unrecognized association between POF and a novel genetic locus or region of unknown nature on 8q22.3. We speculate existence of a long- distance regulatory region that has relevance to the control of ovarian differentiation or oogenesis.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.