Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Free Access

A Rare Variant in CACNA1D Segregates with 7 Bipolar I Disorder Cases in a Large Pedigree

Ross J.a · Gedvilaite E.b · Badner J.A.d · Erdman C.a · Baird L.e · Matsunami N.e · Leppert M.e · Xing J.b, c · Byerley W.a

Author affiliations

aDepartment of Psychiatry, University of California, San Francisco, Calif., bDepartment of Genetics and cHuman Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, N.J., dDepartment of Psychiatry, University of Chicago, Chicago, Ill., and eDepartment of Human Genetics, University of Utah, Salt Lake City, Utah, USA

Corresponding Author

William Byerley, MD

401 Parnassus

University of California, San Francisco

San Francisco, CA 94143 (USA)

E-Mail william.byerley@ucsf.edu

Related Articles for ""

Mol Neuropsychiatry 2016;2:145-150

Do you have an account?

Login Information

Contact Information

By signing up for MyKarger you will automatically participate in our year-End raffle.
If you Then Do Not wish To participate, please uncheck the following box.

Yes, I wish To participate In the year-End raffle And Get the chance To win some Of our most interesting books, And other attractive prizes.

I have read the Karger Terms and Conditions and agree.


Whole-genome sequencing was performed on 3 bipolar I disorder (BPI) cases from a multiplex pedigree of European ancestry with 7 BPI cases. Within CACNA1D, 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.

© 2016 S. Karger AG, Basel


  1. Craddock N, Sklar P: Genetics of bipolar disorder. Lancet 2013;381:1654-1662.
  2. Byerley W, Badner JA: Strategies to identify genes for complex disorders: a focus on bipolar disorder and chromosome 16p. Psychiatr Genet 2011;21:173-182.
  3. Edenberg HJ, Foroud T, Conneally PM, Sorbel JJ, Carr K, Crose C, Willig C, Zhao J, Miller M, Bowman E, Mayeda A, Rau NL, Smiley C, Rice JP, Goate A, Reich T, Stine OC, McMahon F, DePaulo JR, Meyers D, Detera-Wadleigh SD, Goldin LR, Gershon ES, Blehar MC, Nurnberger JI Jr: Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 3, 5, 15, 16, 17, and 22. Am J Med Genet 1997;74:238-246.
  4. Kelsoe JR, Spence MA, Loetscher E, Foguet M, Sadovnick AD, Remick RA, Flodman P, Khristich J, Mroczkowski-Parker Z, Brown JL, Masser D, Ungerleider S, Rapaport MH, Wishart WL, Luebbert H: A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 2001;98:585-590.
  5. Etain B, Mathieu F, Rietschel M, Maier W, Albus M, McKeon P, Roche S, Kealey C, Blackwood D, Muir W, Bellivier F, Henry C, Dina C, Gallina S, Gurling H, Malafosse A, Preisig M, Ferrero F, Cichon S, Schumacher J, Ohlraun S, Borrmann-Hassenbach M, Propping P, Abou Jamra R, Schulze TG, Marusic A, Dernovsek ZM, Giros B, Bourgeron T, Lemainque A, Bacq D, Betard C, Charon C, Nöthen MM, Lathrop M, Leboyer M: Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14. Mol Psychiatry 2006;11:685-694.
  6. Psychiatric GWAS Consortium Bipolar Disorder Working Group: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011;43:977-983.
  7. Chen DT, Jiang X, Akula N, Shugart YY, Wendland JR, Steele CJ, Kassem L, Park JH, Chatterjee N, Jamain S, Cheng A, Leboyer M, Muglia P, Schulze TG, Cichon S, Nöthen MM, Rietschel M; BiGS, McMahon FJ, et al: Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol Psychiatry 2013;18:195-205.
  8. Schizophrenia Working Group of the Psychiatric Genomics Consortium: Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421-427.
  9. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK; DDD Study; Homozygosity Mapping Collaborative for Autism; UK10K Consortium, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD: Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014;515:209-215.
  10. Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A, He W, Chen YJ, Makhijani V, Roth GT, Gomes X, Tartaro K, Niazi F, Turcotte CL, Irzyk GP, Lupski JR, Chinault C, Song XZ, Liu Y, Yuan Y, Nazareth L, Qin X, Muzny DM, Margulies M, Weinstock GM, Gibbs RA, Rothberg JM: The complete genome of an individual by massively parallel DNA sequencing. Nature 2008;452:872-876.
  11. DNA sequencing costs. National Human Genome Research Institute. http://www.genome.gov/sequencingcosts.
  12. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, O'Dushlaine C, Chambert K, Bergen SE, Kähler A, Duncan L, Stahl E, Genovese G, Fernández E, Collins MO, Komiyama NH, Choudhary JS, Magnusson PK, Banks E, Shakir K, Garimella K, Fennell T, DePristo M, Grant SG, Haggarty SJ, Gabriel S, Scolnick EM, Lander ES, Hultman CM, Sullivan PF, McCarroll SA, Sklar P: A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014;506:185-190.
  13. Zuk O, Schaffner SF, Samocha K, Do R, Hechter E, Kathiresan S, Daly MJ, Neale BM, Sunyaev SR, Lander ES: Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci USA 2014;111:455-464.
  14. Wang Q, Lu Q, Zhao H: A review of study designs and statistical methods for genomic epidemiology studies using next generation sequencing. Front Genet 2015;6:149.
  15. Endicott J, Spitzer RL: A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978;35:837-844.
  16. Spitzer RL, Endicott J, Robins E: Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 1978;35:773-782.
  17. Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ: Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 2010;328:636-639.
  18. Hu H, Huff CD, Moore B, Flygare S, Reese MG, Yandell M: VAAST 2.0: improved variant classification and disease-gene identification using a conservation-controlled amino acid substitution matrix. Genet Epidemiol 2013;37:622-634.
  19. Shihab HA, Gough J, Mort M, Cooper DN, Day IN, Gaunt TR: Ranking non-synonymous single nucleotide polymorphisms based on disease concepts. Hum Genomics 2014;8:11-17.
  20. Wang K, Li M, Hakonarson H: ANNOVAR: functional annotation of genetic variants from next-generation sequencing data. Nucleic Acids Res 2010;38:164-171.
  21. Flanagan SE, Patch AM, Ellard S: Using SIFT and PolyPhen to predict loss-of- function and gain-of-function mutations. Genet Test Mol Biomarkers 2010;14:533-537.
  22. Vossen RH, Aten E, Roos A, den Dunnen JT: High-resolution melting analysis (HRMA): more than just sequence variant screening. Hum Mutat 2009;30:860-866.
  23. Catterall WA, Few AP: Calcium channel regulation and presynaptic plasticity. Neuron 2008;59:882-901.
  24. Calin-Jageman I, Lee A: Ca(v)1 L-type Ca2+ channel signaling complexes in neurons. J Neurochem 2008;105:573-583.
  25. Casamassima F, Hay AC, Benedetti A, Lattanzi L, Cassano GB, Perlis RH: L-type calcium channels and psychiatric disorders: a brief review. Am J Med Genet B Neuropsychiatr Genet 2010;8:1373-1390.
  26. Pennartz CMA, de Jeu MTG, Bos NPA, Schaap J, Geurtsen AMS: Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 2002;416:286-290.
  27. Ament SA, Szelinger S, et al: Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc Natl Acad Sci USA 2015;112:3576-3581.

Article / Publication Details

Received: February 02, 2015
Accepted: June 28, 2016
Published online: August 03, 2016
Issue release date: October 2016

Number of Print Pages: 6
Number of Figures: 1
Number of Tables: 0

ISSN: 2296-9209 (Print)
eISSN: 2296-9179 (Online)

For additional information: https://www.karger.com/MNP

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.