see also:

• cardiology

• a study of AI analysis of GWAS and cardiac indices was published in March 2024 which revealed a range of genetic associations including 40 new loci associations, a sub-group of these are outlined below. ¹⁾

• intergenic SNP rs11153730
  • probably related to PLN
  • PLN plays a crucial role in cardiomyocyte calcium handling by acting as a primary regulator of the SERCA protein (sarco- or endoplasmic reticulum Ca2+-ATPase), which transports calcium from the cytosol into the SR1
  • mutations in PLN have a well-established relationship with dilated cardiomyopathy (DCM)
  • PLN was found to be associated with LVEDV and LVESV
• locus on chromosome 2 (with lead SNP rs2042995)
  • known to be associated with TTN
  • this gene encodes the protein titin, which is responsible for assembling myocyte sarcomere, and determines the stretching, contraction and passive stiffness of the myocardium
• rs375034445 lies within the body of BAG3
  • a well-known cardiac gene coding for a cellular protein that is predominantly expressed in skeletal and cardiac muscle, which plays a role in myocyte homeostasis and in the development of heart failure
  • shows a stronger association with LVESV and LV ejection fraction (LVEF)
• locus near the ATXN2 gene
  • associated with LVEDV and stroke volume (SV)
  • a candidate casual gene for this association is gene MYL2, the lead SNP (rs35350651) lies 558808 base pairs away from this gene’s transcription start site (TSS)
• gene TMEM43
  • association with LVESV and LVEF
• gene MYH6 harbours SNP rs365990
  • this gene provides instructions for making a protein known as the cardiac α-myosin heavy chain, which is expressed throughout the myocardium during early cardiac development
  • mutations in this gene, as well as the neighbouring MYH7 responsible for the β-myosin heavy chain, have been linked to several pathologies: cardiomyopathies, arrhythmias and congenital heart disease (CHD)
• Two additional associations are located close to genes RRAS2 and ATG4D

• nine additional independent associations found, apart from the PLN locus
• rs35564079
  • is located 8,250 bp upstream of the TSS of NKX2-5, in chromosome 5
  • NKX2-5 plays a crucial role in heart development; in particular, in the formation of the heart tube, which is a structure that will eventually give rise to the heart and great vessels
  • NKX2-5 helps determine the heart’s position in the chest and also develops the heart valves and septa
  • mutations in the NKX2-5 gene have been associated with several types of congenital heart defect, including atrial septal defects and atrioventricular block
• rs72007904
  • is located 300 kb upstream of the TSS of the gene ABRA
  • ABRA codes for a cardiac and skeletal muscle-specific actin-binding protein located in the Z disc and M-line and binds with actin
  • it is differentially expressed in cardiac tissues and skeletal muscle
  • ABRA has been associated with DCM in mic
• rs35001652
  • is close to KDM1A, a gene that codes for a histone demethylase involved in cardiac development, according to studies in mice
• rs463106
  • lies in the body of gene PRDM6
  • the mouse homologue of this gene, Prdm6, has been found to be important in early cardiac development
• SNP rs162746
  • is close to gene EN1
• rs573709385
  • lies in a gene desert in chromosome 2 - the closest protein-coding genes are ACVR2A and ZEB2

• rs4767239
  • is probably related to developmental gene TBX5 (T-box transcription factor 5), which has a known role in developing the heart and the limbs
  • mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs
• locus near the CENPW gene
  • has a cardiac gene, HEY2, possibly causal for this association
  • HEY2 has been shown to suppress cardiac hypertrophy through an inhibitory interaction with GATA4, a transcription factor that plays a key role in cardiac development and hypertrophy
  • HEY proteins are direct targets of Notch signalling and have been shown to regulate multiple key steps in cardiovascular development
  • loss of HEY2 in mice leads to cardiac defects with high postnatal lethality
  • this locus has also been reported as associated to right-ventricular phenotypes
• rs3740293
  • overlaps gene SYNPO2L, which is highly expressed in cardiac tissues (LV and atrial appendage) and skeletal muscle, making it a strong candidate gene
  • is also close to gene MYOZ1
  • both genes have been previously proposed as candidates for cardiac phenotypes, in particular atrial fibrillation, however, MYOZ1 shows very high expression only in the latter
  • loss-of-function variants in this SYNPO2L have also been found causative of atrial fibrillation supporting this gene as a more likely candidate
• rs73243622
  • close to the candidate gene PPARGC1A
• gene CDKN1A
  • association with LVESV and LVEF

• three new loci were found, apart from the PLN locus
• rs2070458
  • close to SMARCB1 (in chromosome 22)
• rs17460016
  • in the FNDC3B locus (in chromosome 3)
• rs12542527
  • in chromosome 8
  • this is an eQTL for the MTSS1 gene also linked to LV fractal dimension