Genome-wide linkage analysis of congenital heart defects using MOD score analysis identifies two novel loci

Abstract

BackgroundCongenital heart defects (CHD) is the most common cause of death from a congenital structure abnormality in newborns and is often associated with fetal loss. There are many types of CHD. Human genetic studies have identified genes that are responsible for the inheritance of a particular type of CHD and for some types of CHD previously thought to be sporadic. However, occasionally different members of the same family might have anatomically distinct defects — for instance, one member with atrial septal defect, one with tetralogy of Fallot, and one with ventricular septal defect. Our objective is to identify susceptibility loci for CHD in families affected by distinct defects. The occurrence of these apparently discordant clinical phenotypes within one family might hint at a genetic framework common to most types of CHD.ResultsWe performed a genome-wide linkage analysis using MOD score analysis in families with diverse CHD. Significant linkage was obtained in two regions, at chromosome 15 (15q26.3, Pempirical = 0.0004) and at chromosome 18 (18q21.2, Pempirical = 0.0005).ConclusionsIn these two novel regions four candidate genes are located: SELS, SNRPA1, and PCSK6 on 15q26.3, and TCF4 on 18q21.2. The new loci reported here have not previously been described in connection with CHD. Although further studies in other cohorts are needed to confirm these findings, the results presented here together with recent insight into how the heart normally develops will improve the understanding of CHD.

Small supernumerary marker chromosome 15 and a ring chromosome 15 associated with a 15q26.3 deletion excluding the IGF1R gene

“…SELS ( selenoprotein S , VIMP ) (*607918) gene was associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD) (Alanne et al, ; Cox et al, ). In addition to the previous results (Flaquer et al, ) attempted to identify the chromosomal regions that could be implicated in a possible common genetic framework shared by distinct types of CHD. He found two linkage regions, on chr15 and 18, and reported that SELS ( selenoprotein S ) , SNRPA1 ( small nuclear ribonucleoprotein polypeptide A1 ) (*603521), and PCSK6 (proprotein convertase subtilisin/kexin type 6 ) (*167405) as candidate genes on chr15 could be responsible for the development of different types of CHD (Flaquer et al, ).…”

“…In addition to the previous results (Flaquer et al, ) attempted to identify the chromosomal regions that could be implicated in a possible common genetic framework shared by distinct types of CHD. He found two linkage regions, on chr15 and 18, and reported that SELS ( selenoprotein S ) , SNRPA1 ( small nuclear ribonucleoprotein polypeptide A1 ) (*603521), and PCSK6 (proprotein convertase subtilisin/kexin type 6 ) (*167405) as candidate genes on chr15 could be responsible for the development of different types of CHD (Flaquer et al, ). Our findings about the SELS , SNRPA1 , and PCSK6 genes confirm the previously reported results by (Alanne et al, ; Cox et al, ; Flaquer et al, )that these genes could be associated with the development of the ASD/VSD.…”

“…He found two linkage regions, on chr15 and 18, and reported that SELS ( selenoprotein S ) , SNRPA1 ( small nuclear ribonucleoprotein polypeptide A1 ) (*603521), and PCSK6 (proprotein convertase subtilisin/kexin type 6 ) (*167405) as candidate genes on chr15 could be responsible for the development of different types of CHD (Flaquer et al, ). Our findings about the SELS , SNRPA1 , and PCSK6 genes confirm the previously reported results by (Alanne et al, ; Cox et al, ; Flaquer et al, )that these genes could be associated with the development of the ASD/VSD. Summarizing, CHD frequently occurs in patients with r(15) associated with terminal deletions but the exact cause of the clinical manifestations has not been elucidated.…”

Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice

“…Previous studies have also reported that PCSK6 is of importance for the processing and activation of growth factors, primarily TGFB1 and PDGFB [22][23][24][25]. The influence of PCSK6 on the cardiovascular system and disease development still remains largely unknown, although variants in the PCSK6 genomic locus have been associated with congenital heart disease and aortic dissection [26,27] and PCSK6 has been implicated as a regulator of blood pressure in mice subjected to a sodium chloride enriched diet [28]. Utilizing a large human Biobank of Karolinska Endarterectomies, we have previously shown that upregulation of PCSK6 is associated with atherosclerotic plaque instability in patients with carotid stenosis [29].…”

Fast Linkage Analysis with MOD Scores Using Algebraic Calculation

“…Our group has implemented the MOD-score approach, including a routine to perform simulations under the null hypothesis, in the GENEHUNTER-MODSCORE (GHM) software [10][11][12][13] . Its application has led to the identification of a variety of genetic disease loci [14][15][16][17][18] .…”