Association between maternal genome-wide polygenic scores for psychiatric and neurodevelopmental disorders and perinatal risk factors: A Danish population-based study
Authors: Ge Fenfen , Wang Yue , Liu Xiaoqin , Munk-Olsen Trine , Madsen Kathrine Bang , Pedersen Emil Michael , Albiñana Clara , Agerbo Esben , Bulik Cynthia M. , Petersen Liselotte Vogdrup , Valdimarsdottir Unnur A. , Vilhjálmsson Bjarni Jóhann 
Published: January 2025

Importance

Adverse perinatal outcomes are common challenges for mothers and their newborns. Epidemiological studies indicate that mothers with psychiatric and neurodevelopmental disorders are at an increased risk of adverse pregnancy and neonatal outcomes; however, the underlying mechanisms behind these associations remain inadequately understood.

Objective

To investigate whether perinatal risk factors are driven by maternal genetic susceptibility to multiple psychiatric and neurodevelopmental disorders.

Design, setting and participants

This nationwide population-based case-control study identified 14,917 primiparous mothers with available genetic information, born between 1981 and 2008, from the iPSYCH cohort, which is nested in the Danish National Registers.

Exposures

Eight genome-wide polygenic scores (PGS) for psychiatric and neurodevelopmental disorders in mothers—ADHD, autism spectrum disorder (ASD), schizophrenia, depression, anxiety, bipolar disorder, obsessive-compulsive disorder, and anorexia nervosa—were calculated using LDPred2.

Main outcomes and measures

Six pregnancy-related and four neonatal-related risk factors were obtained from the Danish Medical Birth Registry. Odds ratios (ORs) and 95% CIs were estimated, adjusted for the year of delivery and the first 10 genetic principal components.

Results

Of 14,917 mothers, the mean age at childbirth was 24.9 years (standard deviation [SD]=3.9). Per SD increase in the PGS for ADHD (OR=1.07 [95%CI 1.00-1.14]), anxiety (1.10 [1.03-1.18]) and depression (1.12 [1.05-1.20]) were associated with maternal smoking exceeding 10 cigarettes per day during the early pregnancy. Stronger associations were observed for the depression PGS in relation to younger age at first birth (i.e. < 20 years; 1.15 [1.07-1.23]), mandatory education (1.15 [1.11-1.19]), and non-cohabitation status during pregnancy (1.07 [1.02-1.12]), compared to other PGS. Schizophrenia PGS was associated with reduced odds of maternal obesity (0.88 [0.84-0.93]) during early pregnancy. In contrast, little evidence was found for associations between maternal PGS for psychiatric and neurodevelopmental disorders and neonatal-related risk factors. We observed comparable associations when the analyses excluded mothers with any psychiatric or neurodevelopmental disorders prior to the conception date.

Conclusions and relevance

High genetic loading for psychiatric and neurodevelopmental disorders may partly explain the observed phenotypic associations between maternal mental illness and perinatal risk factors, particularly pregnancy related factors, but it is less likely to account for associations with neonatal related factors. Alternative mechanisms, e.g., psychological stress and medical treatment for psychiatric and neurodevelopmental disorders, should be further explored.