A rare missense variant in RCL1 segregates with depression in extended families

Abstract

Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, β_T-allele=2.33, P-value=1 × 10^-4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, β_T-allele=3.60, P-value=3 × 10^-2). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.

Figure 1

All carriers of c.1114C>T in the Erasmus Rucphen Family (ERF) study. Males are depicted with squares and females with circles. The text below each individual shows his/her age followed by the score on HADS-D scale, genotype and psychiatric diagnosis (mdd refers to major depressive disorder/lifetime depression and mild refers to depression not otherwise specified), if any. Individuals connected with dotted lines are duplicates. Dots indicate missing values. HADS, Hospital Anxiety Depression Scale.

Figure 2

Immunohistochemical labeling of RCL1 in human cerebral cortex. (a) Overview of RCL1 labeling showing co-localization with long (>350 μm) tortuous interlaminar GFAP-positive extensions (the dashed line marks the approximate border between cortical layers I and II, scale bar=50 μm). (b) Higher magnification of marked region in a (scale bar=12 μm).