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, βT-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, βT-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.

Whole-Genome Linkage Scan Combined With Exome Sequencing Identifies Novel Candidate Genes for Carotid Intima-Media Thickness

“…However, despite these distinct advantages, we were able to identify a genetic variant for only one of the several linked genomic regions, for which, there may be several reasons including structural variants, and intronic or intergenic single-nucleotide variants that were not evaluated in the current study. Interestingly, the 19q13.43, 20p13, and 21q22.12 linkage peaks were previously associated with various phenotypes in our study population including personality traits and depressive symptoms ( Amin et al, 2012 , 2017b ).…”

“…However, this approach has been demonstrated as successful for some other quantitative traits. Following the same approach as described in our study, Amin et al (2018) successfully identified a rare variant of large effect in large extended families. To discover such variants in the extremes of cIMT distribution, we performed affected-only genome-wide linkage analysis of cIMT followed by fine-mapping using exome sequencing in a large family-based study from a genetically isolated population in the Netherlands.…”

Genome scans of dog behavior implicate a gene network underlying psychopathology in mammals, including humans

“…Here it was associated with chasing in two cohorts and anxiety traits in single cohorts. Human linkage and association studies showed a missense mutation in RCL1 is associated with depression 29 . ANGPT1 is very near the chr13 peak associated with excitability, nonsocial fear and body size in two cohorts and with dog aggression, separation anxiety, attachment and lifespan in single cohorts.…”

Genome wide association analysis identifies genetic variants associated with reproductive variation across domestic dog breeds and uncovers links to domestication

“…RCL1 functions in the maturation of 18s RNA (Lyng et al 2006) and is associated with cervical cancer; one role of the gene in this cancer pathology is thought to involve the regulation of insulin receptors (Lyng et al 2006). Additionally, a rare missense variation in RCL1 was recently associated with depression (Amin et al 2017).…”