title: Copy number variants encompassing Mendelian disease genes in a large multigenerational family segregating bipolar disorder.
abstract: BACKGROUND
  Bipolar affective disorder (BP) is a common, highly heritable psychiatric disorder characterized by periods of depression and mania. Using dense SNP genotype data, we characterized CNVs in 388 members of an Old Order Amish Pedigree with bipolar disorder. We identified CNV regions arising from common ancestral mutations by utilizing the pedigree information. By combining this analysis with whole genome sequence data in the same individuals, we also explored the role of compound heterozygosity.
  
  
  RESULTS
  Here we describe 541 inherited CNV regions, of which 268 are rare in a control population of European origin but present in a large number of Amish individuals. In addition, we highlight a set of CNVs found at higher frequencies in BP individuals, and within genes known to play a role in human development and disease. As in prior reports, we find no evidence for an increased burden of CNVs in BP individuals, but we report a trend towards a higher burden of CNVs in known Mendelian disease loci in bipolar individuals (BPI and BPII, p = 0.06).
  
  
  CONCLUSIONS
  We conclude that CNVs may be contributing factors in the phenotypic presentation of mood disorders and co-morbid medical conditions in this family. These results reinforce the hypothesis of a complex genetic architecture underlying BP disorder, and suggest that the role of CNVs should continue to be investigated in BP data sets.
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. rkember@mail.med.upenn.edu.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Kember
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. bgeorgi@mail.med.upenn.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Georgi
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA. jebw@mail.nih.gov.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.affiliation: Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA. stamboli@mail.med.upenn.edu.
authors.forename: Dwight
authors.initials: D
authors.lastname: Stambolian
authors.affiliation: Appel Alzheimer's Disease Research Institute, Mind and Brain Institute, Weill Cornell Medical College, New York, NY, USA. smpaulmd@gmail.com.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. bucan@upenn.edu.|Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. bucan@upenn.edu.
authors.forename: Maja
authors.initials: M
authors.lastname: Bućan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061365:Amish / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide