title: A Rare Variant inCACNA1DSegregates with 7 Bipolar I Disorder Cases in a Large Pedigree.
abstract: Whole-genome sequencing was performed on 3 bipolar I disorder (BPI) cases from a multiplex pedigree of European ancestry with 7 BPI cases. WithinCACNA1D, a gene implicated by genome-wide association studies, a G to C nucleotide transversion at 53,835,340 base pairs (bps) was found predicting the substitution of proline for alanine at amino acid position 1751 (A1751P). Using Sanger sequencing, the DNA variant was shown to co-segregate with the remaining 4 BPI cases within the pedigree. A high-resolution DNA denaturing curve method was then used to screen for the presence of the A1751P change in 4,150 BPI cases from the NIMH Genetics Initiative. The A1751P variant was found in 4 BPI cases. A second variant within exon 43, a C to T nucleotide transition, was found in 1 case at 53,835,355 bps, predicting the substitution of tryptophan for arginine at amino acid position 1771 (R1771W). In the NHLBI Exome Sequencing Project database, the heterozygous A1751P variant was present in 3 of 4,300 subjects of European ancestry, and the R1771W change was not present in any subject. Given the rarity of these variants, large-scale case/control rare variant sequencing studies will be required for definitive conclusions.
authors.affiliation: Department of Psychiatry, University of California, San Francisco, Calif., USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ross
authors.affiliation: Department of Genetics, Rutgers, the State University of New Jersey, New Brunswick, N.J., USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Gedvilaite
authors.affiliation: Department of Psychiatry, University of Chicago, Chicago, Ill., USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Badner
authors.affiliation: Department of Psychiatry, University of California, San Francisco, Calif., USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Erdman
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Baird
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Nori
authors.initials: N
authors.lastname: Matsunami
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Leppert
authors.affiliation: Department of Genetics, Rutgers, the State University of New Jersey, New Brunswick, N.J., USA; Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, N.J., USA.
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Psychiatry, University of California, San Francisco, Calif., USA.
authors.forename: William
authors.initials: W
authors.lastname: Byerley
keywords: Bipolar I disorder; Calcium channel; Rare variant; Whole-genome sequencing