SUPR
Cross-species obsessive compulsive disorder (OCD) and Evolutionary Constraint Analysis
Dnr:

NAISS 2023/5-396

Type:

NAISS Medium Compute

Principal Investigator:

Matteo Bianchi

Affiliation:

Uppsala universitet

Start Date:

2023-10-01

End Date:

2024-10-01

Primary Classification:

30107: Medical Genetics

Allocation

Abstract

The current project aims to complement on-going collaborative studies of multifactorial human OCD, using canine compulsive disorder (CCD) as a genetic model. Here we will leverage our new dog reference genome (UU_Cfam_GSD_1.0) (PMID:33568770) and canine genetic panels (Dog10K) to analyse the genetics of compulsive disorders in many thousands of mix breed dogs. Specifically, we will map additional canine loci in a larger data set by utilising the low-pass sequencing data from Darwin’s Ark resource (~2000 samples, PMID:35482869). We plan to realign these data to the new dog genome assembly generated by our lab (UU_Cfam_GSD_1.0) (PMID:33568770). We will subsequently perform calling and filtering of the detected genetic variation. To augment our data, we will also carry out genetic imputation including the ~2000 genomes from the Dog10K project data (http://www.dog10kgenomes.org/) in the reference panel using existing methods (e.g. PMID: 34498136). With the resulting genetic data in place, we plan to firstly run a genome-wide association study (GWAS) and a gene-based aggregate burden test in order to explore the contribution of common and rare variants, respectively. Starting from the results of these analyses, we will develop tailored methodologies and perform cross-species meta-analysis using human summary statistics (non-sensitive aggregate data) derived from existing human OCD GWAS and gene-based aggregate tests. We also plan to use Zoonomia mammalian constraint scores (https://zoonomiaproject.org) to identify candidate functional variants within both canine and human regions of association and test for enrichment of compulsion-associated loci for mammalian-conserved, primate-conserved, and human-diverged regions.