Genealogical Study of Primary Ovarian Insufficiency Suggests Strong Genetic Component

There may be a strong genetic component to primary ovarian insufficiency (POI), according to the results of a mutigenerational genealogical study of POI published in Fertility and Sterility that is also the first population-based assessment of familial clustering of POI.

POI, like other fertility-impacting conditions such as early menopause, is thought to be largely genetic. FMR1 (FMRP translational regulator 1) premutations and autoimmune polyglandular syndromes are the most common known genetic causes. However, there is a lack of population-based studies to determine the actual prevalence of familial POI beyond first-degree relatives.

“We hypothesized that POI would exhibit excess familial clustering from first- through third-degree relatives when studied on a population level and would indicate patterns of inheritance,” the authors wrote. The study examined trends in multigenerational genealogical data connected to individuals with electronic medical records (EMRs) indicating POI diagnosis.

Women 40 years or younger with POI were identified by EMRs at the University of Utah Health Science Center and Intermountain Healthcare from 1995 to 2021. Nearly 85% of all Utah residents are treated at these 2 health care systems. The Utah Population Database (UPDB), which links genealogy information to medical record information and other demographic data sources, was used to gauge POI familiality in the study. Eligible individuals had at least 3 generations of data in the system.

There were 1440 confirmed cases of POI in the health care system databases, and 396 of those individuals had 3 generations of data available in the UPDB. These women had 2132 first-degree relatives, 5245 second-degree relatives, and 10,853 third-degree relatives. The risk of POI among relatives was compared with the risk in a control group matched by age, sex, and birthplace.

The rates of POI were significantly higher among relatives of women with POI vs the general population. First-degree relatives of women with POI had a relative risk (RR) of 18.52 compared with the control group, second-degree relatives had an RR of 4.21, and third-degree relatives showed a RR of 2.67. Of the 396 initially identified cases, 6.3% had an affected relative.

Researchers also used the Genealogical Index of Familiality (GIF) to test for excess relatedness compared with matched controls. The GIF measures the average pairwise relatedness of all possible pairs of POI cases compared with the average relatedness of 1000 sets of matched controls. It is used in genealogical research and other familiality studies to assess relatedness of participants.

The GIF results in this study were significant, with POI cases showing a GIF of 5.24 overall and controls showing a GIF of 2.38. Notably, the distant GIF result that only includes third-degree relatives was not significantly different between controls and cases. The GIF statistic was mostly due to close relatives.

Additional relatives with POI were identified through chart review but left out of familiality analyses because they were found through different methodology than the initial group. However, they were added to an analysis of high-risk POI pedigrees.

Overall, there were 49 high-risk pedigrees identified in the study. There were 12 families with a mother and daughter affected, suggesting possible dominant or complex modes of inheritance, and 4 families with affected pairs of sisters, which suggests dominant or recessive heritance. In the rest of the families, the closest relationships were third-degree relatives, suggesting a dominant inheritance pattern with or without incomplete expressivity or a complex pattern of inheritance. In some families, there is evidence of female-only expressivity with the possibility of male carriers.

The findings show excess familality and familial clustering of POI compared with matched controls. First-degree relatives of women with POI were at the greatest risk, but second-degree and third-degree relatives were also at a higher RR than the general population. This study is the largest so far to assess the incidence of POI in close and extended families of individuals with POI.

“This finding supports the concept that ovarian aging has a strong genetic component with heterogeneous inheritance patterns and emphasizes the importance of understanding the heritability of ovarian aging and risks for aberrant pathways,” the authors concluded.

Reference

Verrilli L, Johnstone E, Welt C, Allen-Brady K. Primary ovarian insufficiency has strong familiality: results of a multigenerational genealogical study. Fertil Steril. Published online October 22, 2022. doi:10.1016/j.fertnstert.2022.09.027