👤 Luis M García-Marín

Parkinson's disease (PD) is a genetically complex neurodegenerative disorder. Up to 15% of cases are considered monogenic. However, research on monogenic PD has largely focused on populations of European ancestry, leaving gaps in our understanding of genetic variability in other populations. This study addresses this gap by analysing the allele frequencies of pathogenic and likely pathogenic variants in known monogenic PD genes across eight global populations, using data from the gnomAD database. We compiled a list of 27 genes associated with Mendelian PD from the Online Mendelian Inheritance in Man (OMIM) database, and identified pathogenic and likely pathogenic variants using ClinVar. We then performed pairwise comparisons of allele frequencies across populations included in the gnomAD database. Variants with significant frequency differences were further assessed using in silico pathogenicity predictions. We identified 81 variants across 17 genes with statistically significant allele frequency differences between at least two populations. Variants in Our findings reveal substantial population-specific differences in the allele frequencies of pathogenic variants linked to monogenic PD, emphasising the need for broader genetic studies beyond European populations. These insights have important implications for PD research, genetic screening, and understanding the pathogenesis of PD in diverse populations. Show less

Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e-8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p < .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the associations in chromosomes 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes. Show less

Although snoring is common in the general population, its aetiology has been largely understudied. Here we report a genetic study on snoring (n ~ 408,000; snorers ~ 152,000) using data from the UK Biobank. We identify 42 genome-wide significant loci, with an SNP-based heritability estimate of ~10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism are observed. Gene-based associations identify 173 genes, including DLEU7, MSRB3 and POC5, highlighting genes expressed in the brain, cerebellum, lungs, blood and oesophagus. We use polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n ~ 8000). Mendelian randomization analyses suggest a potential causal relationship between high BMI and snoring. Altogether, our results uncover insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond it being a cardinal symptom of OSA. Show less