High genetic risk tied to gestational diabetes and family history

A study published in Pregnancy highlighted that patients with a positive family history of diabetes and personal history of gestational diabetes mellitus (GDM) have the highest polygenic risk scores (PRSs).¹

One in 10 US pregnancies is impacted by GDM, which has been linked to a greater than 7-fold increase in type 2 DM (T2DM) risk. Being born to a mother with GDM has also been linked to increased T2DM and obesity risks.² PRS may be used to predict diabetes risk, but few studies have used PRS scores with clinical characteristics.¹

“By integrating additional predictive characteristics, such as sociodemographics, behavioral, and biochemical factors, this could improve accuracy for a GDM risk prediction model, and help stratify individuals who may benefit from knowing their PRS to determine optimal intervention strategies,” wrote investigators.

Genetic analysis

The secondary analysis was conducted to evaluate clinical characteristics in PRS quartiles. Patients were recruited from the Hoosier Mom's Cohort, which prioritized patients with a higher GDM risk. Eligibility criteria included being aged at least 18 years with a single gestation of less than 20 weeks.

Patients with any pregestational diabetes, a first-trimester hemoglobin A_1c screening of 6.5% or higher, planned pregnancy termination, chronic systemic steroid use, or major fetal anomalies were excluded from the analysis. Two visits occurred during the prenatal period and at delivery, with survey data and biospecimens collected during these visits.

A QIAsymphony instrument was used to complete DNA extraction, while genotyping was performed using the Infinium Global Diversity Array-8 v1.0. Genetic data were used to validate loci linked to diabetes and assess the performance of reported diabetes PRS. Investigators excluded patients with missing phenotype information.

PRS quartile comparison

There were 391 patients aged a mean 29.7 years and with a mean body mass index of 27.8 included in the final analysis. Of the patients, 16.6% were Hispanic, 71.4% White, and 15.9% Black. A family history of diabetes was reported in 54% and prior GDM in 4.3%. A similar ancestry-adjusted PRS was reported in the cohort vs a large, nulliparous population.

Patients were categorized into 4 quartiles, with quartile 1 indicating the lowest genetic risk and quartile 4 the highest. Maternal characteristics did not significantly differ between PRS quartiles, but quartile 4 had higher rates of family diabetes history and prior GDM, at 61.9% and 8.2%, respectively.

In comparison, a family history of diabetes was reported in 46.4% of quartile 1. Additionally, when comparing quartiles 1 and 2 with quartiles 3 and 4, the higher risk group had increased GDM rates, at 12.8% vs 7.1% in the lower risk group.

Racial and ethnic differences across quartiles

Significant differences in race and ethnicity status were also noted between PRS quartiles. Self-reported racial minority status was reported in 68.1% of quartile 4 vs 3% of quartile 1, and Hispanic ethnicity rates were 29.2% and 9%, respectively.

Lower educational attainment and reduced gestational age at delivery were also reported in quartile 4 vs quartile 1, at 38.1 plus or minus 2.5 weeks vs. 38.7 plus or minus 2.1 weeks, respectively. Additionally, birth weights were 3067.7 vs. 3344.9 g, respectively, and cholesterol levels were 187.9 plus or minus 36.5 vs. 201.7 plus or minus 43.3, respectively.

These results indicated higher GDM rates among patients in higher risk quartiles of GDM. Investigators concluded that this data may be used to inform the development of GDM prevention strategies.

“Using ancestry-adjusted PRS calculations was able to account for differences in baseline demographic characteristics such as race and ethnicity, and thus are likely preferred to isolate the PRS effects on outcomes,” wrote investigators.

References

1. Ellis A, Bhamidipaty-Pelosi S, Aamir M, Kotarski A, Guerrero RF, Haas DM. Diabetes polygenic risk scores and maternal characteristics in Hoosier Moms Cohort participants. Pregnancy. 2025;1(5);e70087. doi:10.1002/pmf2.70087
2. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49-e64. doi:10.1097/AOG.0000000000002501