Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and thalamic radiation white matter microstructure in UK Biobank

Abstract

Background: Major Depressive Disorder (MDD) is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome, and growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide an important route for identification of disease mechanisms by focusing on a specific process excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether MDD polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and the whole genome excluding NETRIN1 pathway genes (genomic-PRS) were associated with white matter integrity. Methods:We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: N = 6,401; MD: N = 6,390). Results:We found significantly lower FA in the superior longitudinal fasciculus (β = -0.035, pcorrected = 0.029) and significantly higher MD in a global measure of thalamic radiations (β = 0.029, pcorrected = 0.021), as well as higher MD in the superior (β = 0.034, pcorrected = 0.039) and inferior (β = 0.029, pcorrected = 0.043) longitudinal fasciculus and in the anterior (β = 0.025, pcorrected = 0.046) and superior (β = 0.027, pcorrected = 0.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. Conclusions:Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for MDD through effects on thalamic radiation white matter microstructure.

White matter microstructure and its relation to longitudinal measures of depressive symptoms in mid-late life

“…There are two potential reasons for the above results. First, deficits in microstructure of the thalamic radiation may be particularly susceptible to the influence by early life factors (43; 44), and second, they may relate to genetic predisposition to depression (17). Although the observational data in the present study did not allow for causal inferences, in future studies, thalamic radiations may be a possibly strong candidate as a causal biomarker for illness.…”

“…In this sample, the mean age of participants was 63.06 years (SD = 7.44) and 47.14% were men. We then conducted further data quality control of the remaining participants, removing outliers(16; 17). Finally, the imaging data was merged with other relevant phenotypic data, including measures of depressive symptoms (steps listed below and presented in Figure S1).…”

“…In the present study, we first investigated the associations between these measures of depressive symptoms and white matter microstructure, due to growing evidence of an association between mood disorders and reductions of white matter microstructure in the limbic system, especially in the thalamic radiations(16; 17). These networks contain important tracts involved in emotional processing(18) and regulation(19), deficits in which are typically associated with the onset and severity of MDD(20).…”

White Matter Microstructure and Its Relation to Longitudinal Measures of Depressive Symptoms in Mid- and Late Life

“…In the current study, we first investigated the associations between these measures of depressive symptoms and white matter microstructure because of the growing evidence of an association between mood disorders and reductions of white matter microstructure in the limbic system, especially in the thalamic radiations (16,17). These networks contain important tracts involved in emotional processing (18) and regulation (19).…”

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood

“…10,11,[13][14][15][16][17][18] In humans, an autosomal-dominant DCC mutation results in structural and functional alterations in the connectivity of mesocortical pathways, with an associated decrease in novelty-seeking behaviour and cigarette use. 19,20 An increasing number of meta-analyses of genome-wide association studies and postmortem human studies have shown that altered levels of DCC expression and the presence of specific genetic polymorphisms in the DCC gene are associated with psychiatric conditions, 21 most notably major depressive disorder, 15,17,[22][23][24][25][26][27][28][29][30][31][32][33][34][35] schizophrenia 34,[36][37][38] and drug abuse. 19,[39][40][41][42] A study by the Cross-Disorder Group of the Psychiatric Genomics Consortium 3 revealed that a PFC-enriched network of genes prominently affected 8 psychiatric disorders, and a DCC single nucleotide polymorphism (SNP) showed the highest pleiotropic association with all 8 disorders.…”