Biomedical subjects

Dale R Nyholt

Publications and source records attributed to Dale R Nyholt.

4 recordsLinked to original sources

PubMed2026

Investigating genetic susceptibility to concussion through rare variants in ion channel and neurotransmission genes.

Some individuals appear more susceptible to concussion or mild traumatic brain injury (mTBI) and the severity, range, and the persistence of post-concussion symptoms vary considerably between affected individuals. Genetic factors are likely to contribute to this variability. Symptomatic overlap of post-concussion syndrome with neurological conditions such as familial hemiplegic migraine (FHM) caused by rare pathogenic variants in ion channel and synapse protein genes, with high sensitivity to head trauma for some patients, suggests that variation in similar pathways may influence concussion susceptibility and recovery. To investigate this hypothesis, we performed whole exome sequencing in 93 unrelated individuals who had sustained a single or multiple concussions and examined rare protein-altering variants in FHM genes, other neuronal ion channel and transporter genes, and genes involved in neurotransmission. We identified 62 different rare missense variants across 24 genes in 59 participants (63%), with 26 individuals carrying 2 or more variants. The prevalence of specific likely damaging rare variants in the 16 ion channel-related genes that were identified was approximately fivefold higher than that observed from gnomAD population controls (Odds Ratio = 5.44, 95% CI [4.13,7.18], P < 0.0001). Notably, voltage-gated calcium and sodium channel genes, including SCN9A, together with neurotransmission-related genes such as SNCAIP, harboured multiple potentially deleterious variants. These findings suggest that rare deleterious variants in genes involved in ion homeostasis and neurotransmission may contribute to an individual's susceptibility to concussion or more severe post-concussion symptoms. This study provides a foundation for future genetic and functional investigations aimed at improving our understanding of concussion susceptibility and outcomes. Further validation in larger cohorts and mechanistic studies is warranted to determine their utility as biomarkers of concussion risk and prognosis.

Humans↗

PubMed2026

Advancements in the Understanding of the Genetics of Obsessive-Compulsive Disorder (OCD).

PURPOSE OF REVIEW: This review summarizes recent advances in the genetics of Obsessive-Compulsive Disorder (OCD), their contribution to understanding disorder biology, and implication for clinical translation. RECENT FINDINGS: Recent GWAS identified 30 genome-wide significant loci and prioritized 25 putatively causal genes. Rare variant studies implicated specific genes, including CHD8, CELSR3, SLITRK5, and QRICH1. Evidence from common and rare variants support brain- and immune-related pathways. Genetic overlap with obsessive compulsive symptoms and other psychiatric disorders indicate shared underlying biology. Current evidence is largely based on individuals of European ancestry, although global efforts are underway to improve ancestral diversity in OCD genetics. Given the urgent need for improved treatment, genetically informed clinical translation approaches hold promise, including pharmacogenetics and drug repurposing. Recent advances in OCD genetics support a highly polygenic architecture, implicate specific neuro-biological and immune pathways, and provide new opportunities for clinical translation.

Humans↗

PubMed2025

Shared genetic risk and causal associations between Post-traumatic stress disorder and migraine with antithrombotic agents and other medications.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that frequently co-occurs with pain disorders including migraine. There are proposed biological, genetic and environmental factors associated with both PTSD and migraine suggesting shared etiology. Genome-Wide Association Studies (GWAS) have been used to identify genomic risk loci associated with various disorders and to investigate genetic overlap between traits. There is a significant genetic correlation between PTSD and migraine with no evidence of a causal relationship that could be attributed to pleiotropy. Cross-disorder genetic analyses were applied to investigate the genetic overlap and causal associations using GWAS summary statistics of PTSD (n = 214408), migraine (n = 873341) and 23 medication use traits (n = 78808-305913) including anti-depressants, anti-migraine preparations and beta-blocking agents. Across the entire genome, anti-thrombotic agents had a significant and negative genetic correlation with PTSD (rG = -0.2, P FDR = 0.032) and a positive genetic correlation with migraine (rG = 0.26, P FDR = 2.23 x 10-8). PTSD showed significant genetic correlation with 11 other medication use traits including beta blocking agents (rG = -0.11, P FDR = 0.034). Of the 2495 genomic regions tested, PTSD showed significant local genetic correlation with 12 medication use traits at 43 loci; while migraine showed significant genetic correlation with only anti-inflammatory agents and anti-rheumatic products at locus 12:57522282-57607142 (DAB1) (P < 2 x 10-5). The genetic liability to PTSD had a causal effect on increased risk of using pain medication such as opioids (β ivw = 0.59, P = 5.21 x 10-5) while the genetic liability to migraine had a causal effect on the increased risk of using anti-thrombotic agents (β ivw = 0.59, P = 1.69 x 10-7). The genes in the genomic regions shared between PTSD and medication use traits were enriched in neural-related pathways such as neuron development, neurogenesis and protein kinase activity. These results provide further insight into the genetically controlled biological and environmental factors underlying the shared etiology between PTSD and migraine. The identified biomarkers can be used as a basis for investigation as potential drug targets for both disorders. These findings are significant for drug re-purposing and treatment of PTSD and migraine using monotherapy.

GWAS↗

PubMed2016

Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

Atlases as Topic↗