Congenital heart disease risk loci identified by genome-wide association study in European patients

Lahm, Harald; Jia, Meiwen; Dreßen, Martina; Wirth, Fabian; Puluca, Nazan; Gilsbach, Ralf; Keavney, Bernard; Cleuziou, Julie; Beck, Nicole; Bondareva, Olga; Dzilic, Elda; Burri, Melchior; König, Karl Christian; Ziegelmüller, Johannes A; Abou‐Ajram, Claudia; Neb, I.; Zhang, Zhong; Doppler, S.; Mastantuono, Elisa; Lichtner, Peter; Eckstein, Gertrud; Hörer, Jürgen; Ewert, Peter; Priest, James R.; Hein, Lutz; Lange, Rüdiger; Meitinger, Thomas; Cordell, Heather J.; Müller‐Myhsok, Bertram; Krane, Markus

doi:10.1172/jci141837

Cited by 51 publications

(48 citation statements)

References 78 publications

(75 reference statements)

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“…On the other hand, MACROD2 resides largely in the cytoplasm [ 31 , 33 ] and is highly expressed in the brain [ 44 ]. Indeed, several genome–wide association studies (GWAS) have reported links between MACROD2 and various neurological and psychiatric conditions such as autism [ 45 ], schizophrenia [ 46 ], ADHD [ 47 ] as well as congenital heart defects [ 48 ] (28% of which are linked to neurodegeneration [ 49 ]). However, there has been some conflicting reports, for example, MACROD2 is considered a hotspot for mutation [ 50 ] and subsequent studies (using different populations, i.e., Chinese) showed no association with autism [ 51 ].…”

Section: Introductionmentioning

confidence: 99%

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice

Crawford

Oliver

Agnew

et al. 2021

Cells

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Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the MACROD2 genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both Macrod1 and Macrod2 gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of Macrod1 resulted in a female-specific motor-coordination defect, whereas Macrod2 disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.

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Section: Introductionmentioning

confidence: 99%

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice

Crawford

Oliver

Agnew

et al. 2021

Cells

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“…The study by Lahm et al [55] also combined GWAS data with hiPSC data and human and animal cellular level data to find support for the results. They showed that the gene with the strongest genome-wide significant SNPs, MACROD2 (associated with TGA), was expressed during cardiac differentiation of hiPSCs, in mouse embryonic cardiogenic tissue and during human embryonic development within ventricular and outflow tract cells [55]. As additional GWASs are performed and the results are added to an already extensive body of literature, meta-analyses have become a standard approach to integrate data across different studies of the same trait [58,59].…”

Section: Genome-wide Association Studiesmentioning

confidence: 96%

“…Thus, it is important to define CHD subtypes considered during analysis clearly. The study by Lahm et al [ 55 ] also combined GWAS data with hiPSC data and human and animal cellular level data to find support for the results. They showed that the gene with the strongest genome-wide significant SNPs, MACROD2 (associated with TGA), was expressed during cardiac differentiation of hiPSCs, in mouse embryonic cardiogenic tissue and during human embryonic development within ventricular and outflow tract cells [ 55 ].…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

“…Generally, GWASs compare the sequence data, or single nucleotide polymorphism (SNP) array intensities, of cases against controls to determine the effect sizes of genetic variants statistically, usually SNPs, on the trait in question. To date, there has been a multitude of GWAS studies on CHD [ 34 , 50 , 51 , 52 , 53 , 54 , 55 ]. However, the generally accepted threshold of genome-wide significance for GWASs ( p < 5 × 10 −8 , [ 56 ]) has been difficult to achieve, often due to relatively small case-cohort sizes (usually less than 1000 individuals).…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

“…As it is known that different CHD lesions have at least partly distinct genetic etiologies, creating subtype categories of CHD can improve the analysis. For example, Lahm et al [ 55 ] demonstrated a significant association of a large cohort of CHD patients with rs185531658, whereas in the same study, other SNPs showed significant association to various sub-groups of the cohort; transposition of the great arteries (TGA, six genome-wide significant variants), right heart lesions (one genome-wide significant variant), left heart lesions (one genome-wide significant variant), and anomalies of thoracic arteries and veins (ATAV, one genome-wide significant variant) [ 55 ]. Thus, it is important to define CHD subtypes considered during analysis clearly.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

See 2 more Smart Citations

From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

Broberg

Hästbacka

Helle

2021

Genes

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Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development.

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A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

Huang,

Lyu,

Liu

et al. 2023

Genetic Epidemiology

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The risk of congenital heart defects (CHDs) may be influenced by maternal genes, fetal genes, and their interactions. Existing methods commonly test the effects of maternal and fetal variants one‐at‐a‐time and may have reduced statistical power to detect genetic variants with low minor allele frequencies. In this article, we propose a gene‐based association test of interactions for maternal–fetal genotypes (GATI‐MFG) using a case‐mother and control‐mother design. GATI‐MFG can integrate the effects of multiple variants within a gene or genomic region and evaluate the joint effect of maternal and fetal genotypes while allowing for their interactions. In simulation studies, GATI‐MFG had improved statistical power over alternative methods, such as the single‐variant test and functional data analysis (FDA) under various disease scenarios. We further applied GATI‐MFG to a two‐phase genome‐wide association study of CHDs for the testing of both common variants and rare variants using 947 CHD case mother–infant pairs and 1306 control mother–infant pairs from the National Birth Defects Prevention Study (NBDPS). After Bonferroni adjustment for 23,035 genes, two genes on chromosome 17, TMEM107 (p = 1.64e−06) and CTC1 (p = 2.0e−06), were identified for significant association with CHD in common variants analysis. Gene TMEM107 regulates ciliogenesis and ciliary protein composition and was found to be associated with heterotaxy. Gene CTC1 plays an essential role in protecting telomeres from degradation, which was suggested to be associated with cardiogenesis. Overall, GATI‐MFG outperformed the single‐variant test and FDA in the simulations, and the results of application to NBDPS samples are consistent with existing literature supporting the association of TMEM107 and CTC1 with CHDs.

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Congenital heart disease risk loci identified by genome-wide association study in European patients

Cited by 51 publications

References 78 publications

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice

From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

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