Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease
Open accessAbstract
Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHD had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 × 10(-5)). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in ~5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., HAND2 and GJA5). Rare genic deletions contribute ~4% of the population-attributable risk of sporadic CHD. Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHD trios exhibit paternal origin bias.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The meta-analysis of CHD case-control studies shows an OR of 4.96 when the small control groups from the original publications are used.
“Our meta-analysis of CHD case–control studies6–8 shows an OR of 4.96 when the small control groups from the original publications are used (figure 1).”
From Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice (2019) · cites this paper as [8]
The 15q11.2 deletion is associated with congenital heart disease.
“The deletion has also been associated with congenital heart disease (CHD).6–8”
From Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice (2019) · cites this paper as [8]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
GREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502 · see citing works
Functional impact of global rare copy number variation in autism spectrum disorders
Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., et al. (2010) · Nature · doi:10.1038/nature09146 · Cited by 2,013 · cited 1× · see citing works
“Previous large studies of CNVs in psychiatric and developmental phenotypes have demonstrated an increased burden of rare CNVs (the greatest effects were observed in single-occurrence and de novo CNVs),(1,2,22) larger CNV size, and higher number of genes spanned by rare CNVs in cases compared to controls.(1,3,4) The st…”
ResultThe Wellcome Trust Case Control Consortium (2010) · Nature · doi:10.1038/nature08979 · Cited by 807 · see citing works
Brunetti-Pierri, N., Berg, J. S., Scaglia, F., Belmont, J., Bacino, C. A., Sahoo, T., Lalani, S. R., Graham, B., Lee, B., Shinawi, M., et al. (2008) · Nature Genetics · doi:10.1038/ng.279 · Cited by 625 · see citing works
Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
de Kovel, C. G. F., Trucks, H., Helbig, I., Mefford, H. C., Baker, C., Leu, C., Kluck, C., Muhle, H., von Spiczak, S., Ostertag, P., et al. (2010) · Brain · doi:10.1093/brain/awp262 · Cited by 445 · see citing works
Multifunctional deadenylase complexes diversify mRNA control
Goldstrohm, A. C., & Wickens, M. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2370 · Cited by 377 · see citing works
Comparative genomics of autism and schizophrenia
Crespi, B., Stead, P., & Elliot, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906080106 · Cited by 262 · see citing works
Doornbos, M., Sikkema-Raddatz, B., Ruijvenkamp, C. A. L., Dijkhuizen, T., Bijlsma, E. K., Gijsbers, A. C. J., Hilhorst-Hofstee, Y., Hordijk, R., Verbruggen, K. T., Kerstjens-Frederikse, W. S. (., et al. (2009) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2009.03.010 · Cited by 165 · see citing works
Singleton deletions throughout the genome increase risk of bipolar disorder
Zhang, D., Cheng, L., Qian, Y., Alliey-Rodriguez, N., Kelsoe, J. R., Greenwood, T., Nievergelt, C., Barrett, T. B., McKinney, R., Schork, N., et al. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.144 · Cited by 148 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Soemedi, R., Topf, A., Wilson, I.J., Darlay, R., Rahman, T., Glen, E., Hall, D., Huang, N., Bentham, J., Bhattacharya, S., et al. (2012). Phenotype-specific effect of chromosome 1q21.1 rear- rangements and GJA5 duplications in 2436 congenital heart The American Journal of Human Genetics 91, 489-501, September 7, 2012 499 disease patients and 6760 controls. Hum. Mol. Genet. 21, 1513-1520.
Cited by
Sorted by citations
Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association
Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Delling, F. N., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000757 · Cited by 9,175 · see citing works
Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association
Benjamin, E. J., Muntner, P., Alonso, A., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Das, S. R., et al. (2019) · Circulation · doi:10.1161/cir.0000000000000659 · Cited by 9,036 · see citing works
Heart disease and stroke statistics-2018 update: a report from the american heart association
Benjamin, E. J., Virani, S. S., Callaway, C. W., Chamberlain, A. M., Chang, A. R., Cheng, S., Chiuve, S. E., Cushman, M., Delling, F. N., Deo, R., et al. (2018) · Circulation · doi:10.1161/cir.0000000000000558 · Cited by 7,146 · see citing works
Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Anderson, C. A. M., Arora, P., Avery, C. L., Baker-Smith, C. M., Beaton, A. Z., Boehme, A. K., Buxton, A. E., et al. (2023) · Circulation · doi:10.1161/cir.0000000000001123 · Cited by 8,300 · see citing works
Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association
Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Alonso, A., Beaton, A. Z., Bittencourt, M. S., Boehme, A. K., Buxton, A. E., Carson, A. P., Commodore-Mensah, Y., et al. (2022) · Circulation · doi:10.1161/cir.0000000000001052 · Cited by 5,987 · see citing works
De novo mutations in histone-modifying genes in congenital heart disease
Zaidi, S., Choi, M., Wakimoto, H., Ma, L., Jiang, J., Overton, J. D., Romano-Adesman, A., Bjornson, R. D., Breitbart, R. E., Brown, K. K., et al. (2013) · Nature · doi:10.1038/nature12141 · Cited by 934 · see citing works
Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of Fallot
Page, D. J., Miossec, M. J., Williams, S. G., Monaghan, R. M., Fotiou, E., Cordell, H. J., Sutcliffe, L., Topf, A., Bourgey, M., Bourque, G., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.313250 · Cited by 189 · see citing works
Self-citationJønch, A. E., Douard, E., Moreau, C., Van Dijck, A., Passeggeri, M., Kooy, F., Puechberty, J., Campbell, C., Sanlaville, D., Lefroy, H., et al. (2019) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2018-105879 · Cited by 75 · see citing works
Mlynarski, E. E., Sheridan, M. B., Xie, M., Guo, T., Racedo, S. E., McDonald-McGinn, D. M., Gai, X., Chow, E. W. C., Vorstman, J., Swillen, A., et al. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.03.007 · Cited by 74 · see citing works
Self-citationFurther phenotypic expansion of 15q11.2 BP1–BP2 microdeletion (Burnside-Butler) syndrome
Jerkovich, A., & Butler, M. (2015) · Journal of Pediatric Genetics · doi:10.3233/pge-14082 · Cited by 20 · see citing works
- Authors
- Soemedi, R., Wilson, I. J., Bentham, J., Darlay, R., Töpf, A., Zelenika, D., Cosgrove, C., Setchfield, K., Thornborough, C., Granados-Riveron, J., Blue, G. M., Breckpot, J., Hellens, S., Zwolinkski, S., Glen, E., Mamasoula, C., Rahman, T. J., Hall, D., Rauch, A., Devriendt, K., Gewillig, M., O’ Sullivan, J., Winlaw, D. S., Bu’Lock, F., Brook, J. D., Bhattacharya, S., Lathrop, M., Santibanez-Koref, M., Cordell, H. J., Goodship, J. A., & Keavney, B. D.
- Affiliations
- Newcastle University (GB)
- Centre for Human Genetics (GB)
- University of Nottingham (GB)
- Glenfield Hospital (GB)
- Children's Hospital at Westmead (AU)
- Universitair Ziekenhuis Leuven (BE)
- University of Zurich (CH)
- KU Leuven (BE)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Corresponding author
- Goodship, Judith A.
- Keavney, Bernard D.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 91
- Issue
- 3
- Pages
- 489-501
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3511986
- OpenAlex
- W2076479322
- Cited by
- 315
- References
- 10
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 25 · 2023: 9 · 2022: 23 · 2021: 21 · 2020: 21 · 2019: 26 · 2018: 20 · 2017: 17 · 2016: 26 · 2015: 42 · 2014: 36 · 2013: 22 · 2012: 2
- FWCI
- 19.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
- Research Explorer (The University of Manchester) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Wellcome Trust (087436, 090532)
- National Institute for Health and Care Research
- British Heart Foundation (RG/08/012/25941, RG/07/010/23676, RG/10/17/28553, PG/07/045/22690)
- Heart Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- congenital heart disease, copy number variation, de novo CNVs, haploinsufficiency, Wnt signaling, 1q21.1, Hand2, connexin 40, population attributable risk, heart development
- MeSH terms
- Child, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 8, Fathers, Female, Heart Defects, Congenital, Humans, Male, Gene Deletion, Gene Dosage, Polymorphism, Single Nucleotide, DNA Copy Number Variations
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
