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)
phenotype associations
LVEDV
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
LV sphericity index at end diastole (LVEDSph)
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
LV myocardial mass (LVM)
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
LV mass-to-volume ratio (LVMVR = LVM/LVEDV)
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