👤 Guroji Purushotham

Sleep traits, including sleep apnoea (SA), insomnia, daytime sleepiness, and snoring, frequently co-occur with cardiometabolic diseases (CMDs), with shared genetic factors suspected to underlie these associations. However, the contribution of shared genetic determinants to these associations is not fully understood. We conducted a genome-wide pleiotropic association study applying sequential genetic methods to identify shared genetic variants, genes, pathways and causal associations between the four sleep traits and seven CMDs, including LDSC, high-definition likelihood analysis, colocalisation, gene-based tests, enrichment analysis and Mendelian randomisation. Next, validation of those pleiotropic variants was performed in individuals from the All of Us and MVP studies. Among 28 pairs of sleep traits and CMDs, 25 showed significant genetic correlations. Pleiotropic analysis identified 754 independent SNPs (691 unique) and 102 colocalized loci (85 unique). Among these, 47 SNPs (44 unique) were validated as significantly associated with both traits in the pairs, and notably, rs429358 (19q13.32, APOE) demonstrated pleiotropic effects across SA, insomnia and type 2 diabetes (T2D). Forty-eight annotated genes were validated by gene-based tests. Shared genes were enriched in phenotypes related to mortality and growth. Pathway analysis highlighted Cushing syndrome, hormone secretion, and cGMP-PKG, Ras and calcium signalling pathways. After adjusting for glycaemic traits and blood pressure, genetically predicted T2D increased risk of SA, sleepiness, and snoring. Conversely, SA was positively associated with heart failure and T2D independently. This study of sleep traits and CMDs reveals shared genetic determinants that may partially explain their epidemiologic association and suggests potential treatment targets. Described in Acknowledgements. Show less

Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disorder affecting the cardiac muscle and exhibits varied clinical symptoms because of genetic heterogeneity. Several disease causing genes have been identified and most code for sarcomere proteins. In the current study, we have carried out clinical and molecular analysis of FHC patients from India. FHC was detected using echocardiography and by analysis of clinical symptoms and family history. Disease causing mutations in the β-cardiac myosin heavy chain (MYH7) and Myosin binding protein C3 (MYBPC3) genes were identified using Polymerase Chain Reaction-Deoxyribose Nucleic Acid (PCR-DNA) sequencing. Of the 55 patient samples screened, mutations were detected in only nineteen in the two genes; MYBPC3 mutations were identified in 12 patients while MYH7 mutations were identified in five, two patients exhibited double heterozygosity. All four MYH7 mutations were missense mutations, whereas only 3/9 MYPBC3 mutations were missense mutations. Four novel mutations in MYBPC3 viz. c.456delC, c.2128G>A (p.E710K), c.3641G>A (p.W1214X), and c.3656T>C (p.L1219P) and one in MYH7 viz. c.965C>T (p.S322F) were identified. A majority of missense mutations affected conserved amino acid residues and were predicted to alter the structure of the corresponding mutant proteins. The study has revealed a greater frequency of occurrence of MYBPC3 mutations when compared to MYH7 mutations. Show less