@article{ZahnleiterUebeEkicietal.2013,
  author    = {Zahnleiter, Diana and Uebe, Steffen and Ekici, Arif B. and Hoyer, Juliane and Wiesener, Antje and Wieczorek, Dagmar and Kunstmann, Erdmute and Reis, Andr{\´e} and Doerr, Helmuth-Guenther and Rauch, Anita and Thiel, Christian T.},
  title     = {Rare Copy Number Variants Are a Common Cause of Short Stature},
  series = {PLoS Genetics},
  volume    = {9},
  journal   = {PLoS Genetics},
  number    = {3},
  issn      = {1553-7404},
  doi       = {10.1371/journal.pgen.1003365},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127645},
  pages     = {e1003365},
  year      = {2013},
  abstract  = {Human growth has an estimated heritability of about 80\%-90\%. Nevertheless, the underlying cause of shortness of stature remains unknown in the majority of individuals. Genome-wide association studies (GWAS) showed that both common single nucleotide polymorphisms and copy number variants (CNVs) contribute to height variation under a polygenic model, although explaining only a small fraction of overall genetic variability in the general population. Under the hypothesis that severe forms of growth retardation might also be caused by major gene effects, we searched for rare CNVs in 200 families, 92 sporadic and 108 familial, with idiopathic short stature compared to 820 control individuals. Although similar in number, patients had overall significantly larger CNVs \((p-value <1 x 10^{-7})\). In a gene-based analysis of all non-polymorphic CNVs >50 kb for gene function, tissue expression, and murine knock-out phenotypes, we identified 10 duplications and 10 deletions ranging in size from 109 kb to 14 Mb, of which 7 were de novo (p < 0.03) and 13 inherited from the likewise affected parent but absent in controls. Patients with these likely disease causing 20 CNVs were smaller than the remaining group (p < 0.01). Eleven (55\%) of these CNVs either overlapped with known microaberration syndromes associated with short stature or contained GWAS loci for height. Haploinsufficiency (HI) score and further expression profiling suggested dosage sensitivity of major growth-related genes at these loci. Overall 10\% of patients carried a disease-causing CNV indicating that, like in neurodevelopmental disorders, rare CNVs are a frequent cause of severe growth retardation.},
  language  = {en}
}
@phdthesis{Schulz2010,
  author    = {Schulz, Sandra},
  title     = {The Contribution of Common and Rare Variants to the Complex Genetics of Psychiatric Disorders},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-50677},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Attention deficit/hyperactivity disorder (ADHD), one of the most frequent childhood-onset, chronic and lifelong neurodevelopmental diseases, affects 5 - 10\% of school - aged children and adolescents, and 4\% of adults. The classified basic symptoms are - according to the diagnostic system DSM-VI - inattentiveness, impulsivity and hyperactivity. Also daily life of patients is impaired by learning problems, relationship crises, conflicts with authority and unemployment, but also comorbidities like sleep - and eating problems, mood - and anxiety disorders, depression and substance abuse disorders are frequently observed. Although several twin and family studies have suggested heritability of ADHD, the likely involvement of multiple genes and environmental factors has hampered the elucidation of its etiology and pathogenesis. Due to the successful medication of ADHD with dopaminergic drugs like methylphenidate, up to now, the search for candidate genes has mainly focused on the dopaminergic and - because of strong interactions - the serotonergic system, including the already analyzed candidate genes DAT1, DRD4 and 5, DBH or 5-HTTLPR. Recently, DNA copy number changes have been implicated in the development of a number of neurodevelopmental diseases and the analysis of chromosomal gains and losses by Array Comparative Genomic Hybridization (Array CGH) has turned out a successful strategy to identify disease associated genes. Here we present the first systematic screen for chromosomal imbalances in ADHD using sub-megabase resolution Array CGH. To detect micro-deletions and -duplications which may play a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution aCGH, a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise four deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolising butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domain-containing protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 alpha subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6), and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a ~3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical FBAT, p = 0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by fMRI links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. Additionally, further candidate genes were examined via Matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). This method enables the analysis of SNPs directly from human genomic DNA without the need for initial target amplification by PCR. All these findings implicate CNVs of behavior-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome. The second part of this work concentrates on MLC1, a gene associated with Megalencephalic leukoencephalopathy with subcortical cysts, located on chromosome 22q13.33. To get more insight in the disease itself, a targeting vector for a conditional knockout mouse was constructed using homologous recombination. Furthermore, MLC1 has been suggested as a risk gene for schizophrenia, especially the periodic catatonia subtype. An initially identified missense mutation was found to be extremely rare in other patient cohorts; however, a recent report again argued for an association of two intronic MLC1 SNPs with schizophrenia and bipolar disorder. A case-control study of these polymorphisms as well as SNPs in the transcriptional control region of MLC1 was conducted in 212 chronic schizophrenic patients, 56 of which suffered from periodic catatonia, 106 bipolar patients, and 284 controls. Both intronic and promoter polymorphisms were specifically and significantly associated with periodic catatonia but not schizophrenia or bipolar disorder in general. A haplotype constructed from all polymorphisms was also associated with periodic catatonia. The MLC1 variation is associated with periodic catatonia; whether it constitutes a susceptibility or a modifier gene has to be determined.},
  subject      = {Aufmerksamkeits-Defizit-Syndrom},
  language  = {en}
}