LAUSR

Background Social withdrawal is present as a trait in the general population and is a common early symptom of neuropsychiatric conditions such as Alzheimer's Disease (AD), Schizophrenia (SCZ) and Major Depressive Disorder (MDD). However, the underlying, biological causes of social withdrawal (as trait or disease state) are still poorly understood and may also differ between diseases. With this study, we aim to elucidate the genetics – and hence the biological etiology – of social withdrawal within the general population and patients with AD, SCZ and MDD. Methods We conducted a Genome-Wide Association Study (GWAS) of social withdrawal in a Dutch general population sample, i.e. 2988 adult participants from the Nijmegen Biomedical Study (NBS). For the GWAS, we used the total score on a social withdrawal measure that was based on the answers to 4 items from the extraversion subscale of the Eysenck's Personality Questionnaire (EPQ) regarding social interaction avoidance, and 3 items from the Autism Spectrum Quotient (AQ) about (lack of) social skills. Based on the GWAS results, gene-wide analyses – i.e. taking into account all SNPs within each gene – were performed. Further, a molecular landscape was built based on the proteins encoded by the genes associated with the most significantly associated SNPs from the social withdrawal GWAS. Results Our social withdrawal measure showed a Cronbach's alpha of 0.693 within the NBS sample. The social withdrawal GWAS on the NBS sample did not result in genome-wide significant SNPs. The top SNPs were rs558196057 (P=1.43E-07) in an intron of AK8, and rs181663926 (P=8.11E-07) in an intron of TSC1. However, gene-wide analysis resulted in a significant association (P=2.30E-06) of the GIT1 gene with social withdrawal, which survived correction for the 17.876 genes tested. The molecular landscape provides some insights into the molecular interactions that are involved in social withdrawal in the general population. Discussion The association of social withdrawal with GIT1 is promising, because it encodes a protein involved in neurite outgrowth and synapse formation. The molecular landscape shows the interactions of GIT1 with other molecules linked to social withdrawal and as such provides clues to the mechanisms underlying social withdrawal in the general population. Future research will focus on analyzing social withdrawal in two other general population samples (i.e. the Leiden sample with 1241 subjects and the UK Biobank sample with 500.000 subjects) and the findings from these studies will be incorporated in the molecular landscape of social withdrawal. Moreover, based on the summary statistics from these GWASs, we will perform polygenic risk score-based analyses to determine the (putative) genetic link(s) between social withdrawal as a general population trait and social withdrawal as a disease state in patients with AD, SCZ and MDD.