De novo and inherited CNVs in MZ twin pairs selected for discordance and concordance on Attention Problems

1] Avera Institute for Human Genetics, Avera Behavioral Health Center, Sioux Falls, SD, USA [2] Department of Psychiatry, University of South Dakota, Sioux Falls, SD, USA.
European journal of human genetics: EJHG (Impact Factor: 4.23). 04/2012; 20(10):1037-43. DOI: 10.1038/ejhg.2012.49
Source: PubMed

ABSTRACT Copy number variations (CNVs) have been reported to be causal suspects in a variety of psychopathologic traits. We investigate whether de novo and/or inherited CNVs contribute to the risk for Attention Problems (APs) in children. Based on longitudinal phenotyping, 50 concordant and discordant monozygotic (MZ) twin pairs were selected from a sample of ∼3200 MZ pairs. Two types of de novo CNVs were investigated: (1) CNVs shared by both MZ twins, but not inherited (pre-twinning de novo CNVs), which were detected by comparing copy number (CN) calls between parents and twins and (2) CNVs not shared by co-twins (post-twinning de novo CNVs), which were investigated by comparing the CN calls within MZ pairs. The association between the overall CNV burden and AP was also investigated for CNVs genome-wide, CNVs within genes and CNVs outside of genes. Two de novo CNVs were identified and validated using quantitative PCR: a pre-twinning de novo duplication in a concordant-unaffected twin pair and a post-twinning deletion in the higher scoring twin from a concordant-affected pair. For the overall CNV burden analyses, affected individuals had significantly larger CNVs that overlapped with genes than unaffected individuals (P=0.008). This study suggests that the presence of larger CNVs may increase the risk for AP, because they are more likely to affect genes, and confirms that MZ twins are not always genetically identical.

Download full-text


Available from: Abdel Abdellaoui, Aug 21, 2015
1 Follower
  • Source
    • ") or the assessment of copy number variants (CNVs; Ehli et al., 2012; Scheet et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene x environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.
    Twin Research and Human Genetics 01/2013; 16(1):1-11. DOI:10.1017/thg.2012.140 · 1.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The classical twin study has been a powerful heuristic in biomedical, psychiatric and behavioural research for decades. Twin registries worldwide have collected biological material and longitudinal phenotypic data on tens of thousands of twins, providing a valuable resource for studying complex phenotypes and their underlying biology. In this Review, we consider the continuing value of twin studies in the current era of molecular genetic studies. We conclude that classical twin methods combined with novel technologies represent a powerful approach towards identifying and understanding the molecular pathways that underlie complex traits.
    Nature Reviews Genetics 07/2012; 13(9):640-53. DOI:10.1038/nrg3243 · 39.79 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: With the desire to assess genetic variation across the lifespan in large-scale collaborative projects, one question is whether inference of copy number (CN) is sensitive to the source of material for deoxyribonucleic acid (DNA) analysis (e.g., blood and buccal) and another question is whether CN is stable as individuals age. Here, we address these questions by applying Affymetrix 6.0 single nucleotide polymorphism (SNP) micro-arrays to 1,472 DNA samples from 710 individuals from the Netherlands Twin Register, including twin and non-twin individuals (372 with buccal and blood derived DNA and 388 with longitudinal data). Similar concordance for CN and genotype inference between samples from the same individual [or from the monozygotic (MZ) co-twins] was found for blood and buccal tissues. There was a small but statistically significant decrease in across-tissue concordance compared with concordance of samples from the same tissue type. No temporal effect was seen on CN variation from the 388 individuals sampled at two time points ranging from 1 to 12 years apart. The majority of our individuals were sampled at age younger than 20 years. Genotype concordance was very high (R 2 > 99%) between co-twins from 43 MZ pairs. For 75 dizygotic (DZ) pairs, R 2 was ≈65%. CN estimates were highly consistent between co-twins from MZ pairs for both deletions (R 2 ≈ 90%) and duplications (R 2 ≈ 86%). For DZ, these were similar for within-individual comparisons, but naturally lower between co-twins (R 2 ≈ 50-60%). These results suggest that DNA from buccal samples perform as well as DNA from blood samples on the current generation of micro-array technologies.
    Twin Research and Human Genetics 09/2012; 15(6):1-9. DOI:10.1017/thg.2012.61 · 1.92 Impact Factor
Show more