Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD

Abstract

Obsessive compulsive disorder (OCD) has a complex etiology that encompasses both genetic and environmental factors. However, to date, despite the identification of several promising candidate genes and linkage regions, the genetic causes of OCD are largely unknown. The objective of this study was to conduct linkage studies of childhood-onset OCD, which is thought to have the strongest genetic etiology, in several OCD-affected families from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The authors used parametric and non-parametric approaches to conduct genome-wide linkage analyses using 5,786 single nucleotide repeat polymorphisms (SNPs) in three CVCR families with multiple childhood-onset OCD-affected individuals. We identified areas of suggestive linkage (LOD score ≥ 2) on chromosomes 1p21, 15q14, 16q24, and 17p12. The strongest evidence for linkage was on chromosome 15q14 (LOD = 3.13), identified using parametric linkage analysis with a recessive model, and overlapping a region identified in a prior linkage study using a Caucasian population. Each CVCR family had a haplotype that co-segregated with OCD across a ~7 Mbp interval within this region, which contains 18 identified brain expressed genes, several of which are potentially relevant to OCD. Exonic sequencing of the strongest candidate gene in this region, the ryanodine receptor 3 (RYR3), identified several genetic variants of potential interest, although none co-segregated with OCD in all three families. These findings provide evidence that chromosome 15q14 is linked to OCD in families from the CVCR, and supports previous findings to suggest that this region may contain one or more OCD susceptibility loci.

Figure 1

Pedigrees included in the linkage analysis. Full black symbols indicate DSM-IV OCD. Half black symbols indicate subclinical OCD. Grey symbols= affected or unknown phenotype. += individuals with genotype data. Circles indicate individuals with sequence data.

Figure 2

Plots of genome-wide LOD and NPL scores for chromosomes where LOD scores (MORGAN) or NPL scores ≥2.0. Panel A: Chromosome 1. Panel B: Chromosome 15. Panel C: Chromosome 16. Plots of LOD and NPL scores for all other chromosomes can be found in the supplementary materials. Dominant=autosomal dominant model. Recessive=autosomal recessive model. Narrow=narrow OCD phenotype. Broad=broad OCD phenotype.

Figure 2

Plots of genome-wide LOD and NPL scores for chromosomes where LOD scores (MORGAN) or NPL scores ≥2.0. Panel A: Chromosome 1. Panel B: Chromosome 15. Panel C: Chromosome 16. Plots of LOD and NPL scores for all other chromosomes can be found in the supplementary materials. Dominant=autosomal dominant model. Recessive=autosomal recessive model. Narrow=narrow OCD phenotype. Broad=broad OCD phenotype.

Figure 3

Haplotypes for family 2 in the region of interest on chromosome 15. Black symbols represent the narrow OCD phenotype. Major segregating haplotype is indicated by black line; minor segregating haplotype is indicated by grey line.