Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study

Axel Krug,A Özge Sungur,Michael Koch,Markus M Nöthen,Markus Wöhr,Martin Lackinger,Till F M Andlauer,Fabian Streit,Stefan Herms,Rainer K.w Schwarting ,Anna Maaser,Gerhard Schratt,Frederike Stein,Stephanie H Witt,Marcella Rietschel,Stefanie Heilmann‐Heimbach ,Sugirthan Sivalingam,Andreas J Forstner,Per Hoffmann,Helene Dukal,Bruno Dietsche,Henrike Rippberger,Dominik Seffer,Tilo Kircher

doi:10.1186/s13229-020-00345-2

Abstract

Advanced paternal age (APA) is a risk factor for several neurodevelopmental disorders, including autism and schizophrenia. The potential mechanisms conferring this risk are poorly understood. Here, we show that the personality traits schizotypy and neuroticism correlated with paternal age in healthy subjects (N = 677). Paternal age was further positively associated with gray matter volume (VBM, N = 342) in the right prefrontal and the right medial temporal cortex. The integrity of fiber tracts (DTI, N = 222) connecting these two areas correlated positively with paternal age. Genome-wide methylation analysis in humans showed differential methylation in APA individuals, linking APA to epigenetic mechanisms. A corresponding phenotype was obtained in our rat model. APA rats displayed social-communication deficits and emitted fewer pro-social ultrasonic vocalizations compared to controls. They further showed repetitive and stereotyped patterns of behavior, together with higher anxiety during early development. At the neurobiological level, microRNAs miR-132 and miR-134 were both differentially regulated in rats and humans depending on APA. This study demonstrates associations between APA and social behaviors across species. They might be driven by changes in the expression of microRNAs and/or epigenetic changes regulating neuronal plasticity, leading to brain morphological changes and fronto-hippocampal connectivity, a network which has been implicated in social interaction.

Highlights

Autism spectrum disorder (ASD) and schizophrenia (SZ) are severe mental disorders with neurodevelopmental origin
Human Study Behavioral data Within the sample of N = 677 subjects, paternal age was linearly correlated with the sum score of the Schizotypal Personality Questionnaire brief version (SPQ-B) and all its subscales
Hippocampal neuronal plasticity and microRNAs In order to identify potential molecular pathways causally involved in ASD-related behavioral phenotypes seen in Advanced paternal age (APA) rats, we studied the expression of miRNAs in the rat hippocampus

Summary

Introduction

Autism spectrum disorder (ASD) and schizophrenia (SZ) are severe mental disorders with neurodevelopmental origin They share substantial molecular genetic and early environmental risks [1,2,3]. An important environmental risk factor for ASD and SZ is advanced paternal age (APA) [4,5,6,7,8]. ASD and SZ share elevated levels of schizotypal personality traits and neuroticism, which go along with difficulties in social life. In healthy subjects, these traits increase the risk for the disorders independent of other risks [10,11,12,13] and they are dimensionally distributed among healthy subjects and patients [14]. Whether APA leads to neuroticism or schizotypy in the offspring, and if so, what the underlying mechanisms are

Methods

Results

Discussion

Conclusion