# Genetic risk for psychiatric disorders and prefrontal lobe thickness in a memory clinic population

## TL;DR

This study explores how genetic risk for psychiatric disorders relates to prefrontal cortex thickness in dementia patients and healthy controls.

## Contribution

It identifies a potential genetic link between schizophrenia risk and reduced prefrontal cortex thickness in Lewy body dementia patients.

## Key findings

- No significant main effects were found between polygenic risk scores and prefrontal cortex thickness overall.
- Higher schizophrenia risk scores were linked to thinner lateral orbitofrontal cortex in dementia with Lewy bodies patients.
- The study suggests a genetic basis for psychotic symptoms in dementia with Lewy bodies.

## Abstract

Psychiatric disorders and dementia share overlapping clinical and genetic factors (e.g., SNCA, CLU, and APOE), and both conditions implicating the prefrontal cortex (PFC). We examined the association between genetic liability for psychiatric disorders and PFC thickness in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and cognitively healthy controls.

We analyzed 2,538 individuals (1,258 AD, 169 DLB, 238 FTD, and 873 controls) from the Amsterdam Dementia Cohort. 3D T1w images were processed with FreeSurfer (version 7.1.1) and labels for PFC correspond to those from the Desikan‐Kiliany atlas. The segmentation of all images were visually quality checked. Polygenic risk scores (PRS) for depression (MDDPRS), bipolar disorder (BDPRS), schizophrenia (SCZPRS), and autism (ASDPRS) were calculated using LDpred2, with weights from independent GWAS. Linear mixed models were used to test associations between PRS and PFC thickness, using PRS*hemisphere, PRS*diagnostic group, age, sex, scanner model, and total gray matter volume as fixed effects and hemisphere as random effect.

No significant main effects were observed between PRS and PFC thickness. Hemisphere did not influence the relationship for BDPRS, SCZPRS, or ASDPRS. MDDPRS interacted with hemisphere in relation to PFC, showing positive associations in the left hemisphere and negative in right, although no association reached significance. SCZPRS interacted with DLB case‐control status in relation to lateral orbitofrontal cortex (OFC) thickness, showing that higher SCZPRS associated with reduced lateral OFC thickness in DLB patients (B=‐0.05, p = 0.003), but not in controls (B=0.003, p = 0.6). Additionally, ASDPRS interacted with FTD in relation to PFC regions, although stratified models did not reach significance.

The finding that SCZPRS is associated with reduced lateral OFC thickness in DLB patients suggests a potential genetic basis for psychotic symptoms in DLB and contributes to understanding the neurobiological overlap between DLB and schizophrenia.