An oligogenic risk model for Gilles de la Tourette syndrome based on whole-genome sequencing data
Borczyk, M.; Fichna, J. P.; Piechota, M.; Gołda, S.; Korostynski, M.; Janik, P.; Zekanowski, C.
Show abstract
Gilles de la Tourette syndrome (GTS) and other Tic Disorders (TDs) have a substantial genetic component with their heritability estimated at between 60 and 80%. Here we propose an oligogenic risk model of TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients, their families, and control samples (n = 278). The model is based on the overrepresentation of coding and non-coding genetic variants in and in the vicinity of genes selected from a set of 84 genes previously indicated as putatively associated with GTS. In the discovery phase, based on a variant burden test between unrelated GTS cases (n = 37) and a database of local allele frequencies 10 genes were selected for the model (CHADL, DRD2, MAOA, PCDH10, HTR2A, SLITRK5, SORCS3, KCNQ5, CDH9, and CHD8). Variants in these genes (n = 7654) with a median minor allele frequency in the non-Finnish European population of 0.02 were integrated into an additive classifier. This risk model was then applied to healthy and GTS-affected individuals from 23 families and 100 unrelated healthy samples from the Polish population (AUC-ROC=0.62, p=0.02). Application of the oligogenic model to a group of patients with other tic disorders revealed a continuous increase of the oligogenic score with healthy individuals with the lowest mean, then patients with other tic disorders, then GTS patients, and finally with severe GTS cases with the highest oligogenic score. Results were also overlapped with Psychiatric Genomics Consortium (PGC) GWAS data and we found no significant overlap between the common variant signal and our oligogenic model (p=0.21). Therefore obtained results were compared with the polygenic risk score built from the PGC GWAS data, which revealed a significant contribution of common variant background in severe GTS cases. Overall, we leveraged WGS data to construct a GTS/TDs risk model based on variants that may cooperatively contribute to the etiology of these disorders. This study provides evidence that typical and severe adult GTS as well as other tic disorders may exist on a single spectrum in terms of their genetic background.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome 94%
- Developing a Phenotype Risk Score for Tic Disorders in a Large, Clinical Biobank 93%
- Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders 92%
Similar papers in this journal
- A novel co-segregating DCTN1 splice site variant in a family with Bipolar Disorder may hold the key to understanding the etiology 92%
- Fish as model systems to study epigenetic drivers in human self-domestication and neurodevelopmental cognitive disorders 91%
- Characterization of the common genetic variation in the Spanish population of Navarre 90%
Similar papers in this journal
- Schizophrenia Risk Alleles Often Affect The Expression of Many Genes and Each Gene May Have a Different Effect On The Risk; A Mediation Analysis. 93%
- Independent Inheritance of Cognition and Bipolar Disorder in a Family Sample 92%
- Rare protein coding variants implicate genes involved in risk of suicide death 91%
Similar papers in this journal
- When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population 94%
- Medical Multimorbidity in Patients with Treatment-Resistant Psychosis and Rare Copy Number Variants: A Retrospective Case Series of 24 Patients 93%
- Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy 92%
Similar papers in this journal
- Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes 92%
- Genetic exploration of the relationship between liability to psychiatric disorders and acne vulgaris 91%
- Assessment of ability of AlphaMissense to identify variants affecting susceptibility to common disease 91%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.