Kirk Wilhelmsen | Department of Genetics

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Kirk Wilhelmsen, MD, PhD
Associate Professor

Research Interests

Dr. Wilhelmsen's laboratory is engaged in the genetic mapping of susceptibility loci for complex traits such as addiction and the positional cloning of genes responsible for neurodegenerative disorders. Although his group has mapped the loci for many traits, Dr. Wilhelmsen's original identification of linkage of the syndrome disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) to 17q21-22 (now called FTDP-17) had a key role in setting the direction for his future research. His attraction to the DDPAC phenotype was the wide clinical spectrum of disease presentation (including dementia, motor neuron disease, parkinsonism, alcoholism and behaviors similar to schizophrenia) seen in individuals with the same mutation. Subsequently, mutations in the tau gene were shown to be responsible for most cases of FTDP-17. Dr. Wilhelmsen's current research activity in this area is devoted to determining how tau mutations produce disease, and the positional cloning of mutations responsible for related disorders.

Dr. Wilhelmsen's long-term interest is in the genetic dissection of complex traits. At UCSF he established a clinical and laboratory program to identify addiction susceptibility genes. He moved to UNC in fall of 2004 to continue this work in the Department of Genetics and the Genome Center. There are few conditions where there is a genetic susceptibility that shows more complex interactions between genes and the environment than addiction. Using genetic epidemiology it has been possible to show a heritable component to alcoholism, nicotine dependence and personality. These studies do not, however, allow us to infer how many genes are involved, how these genes interact with each other, or how the environment affects them. The Wilhelmsen group has been using linkage analysis to map susceptibility loci and determine the phenotype that segregates with the alternative alleles for these loci. By refining the phenotype they hope to have more power to detect the causal sequence variations.

To support the genotyping needs for their studies, Dr. Wilhelmsen's laboratory developed highly automated large-scale genotyping (,which is the currency of genetic analysis) and an informatics infrastructure for data handling and processing. They developed a system that could determine the genotypes of 815 evenly spaced microsatellite markers (3 cM average spacing) for 10 people per day. Linkage analysis for four large-scale family based projects has been completed and loci have been identified for a series of addiction and personality related phenotypes.

The next phase of their work is to use association analysis to identify the sequence variations that are responsible for addiction related behaviors. This work requires the genotyping and association analysis of thousands of simple sequence polymorphisms. A logical extension of this work is to develop the ability to perform genome-wide association analysis, which is being used to identify common sequence variations that affect susceptibility to neurodegeneration.

Publications

1. Wilhelmsen KC, Leibowitz JL, Bond CW, Robb JA: The replication of murine coronaviruses in enucleated cells. Virology 110:225-230, 1981

2. Leibowitz JL, Wilhelmsen KC, Bond CW: The virus-specific intracellular RNA species of two murine coronaviruses: MHV-A59 and MHV-JHM. Virology 1981 114:39-51

3. Chen ISY, Wilhelmsen KC, Temin HM: Structure and expression of c-rel (chicken), the cellular homolog to the oncogene of reticuloendotheliosis virus strain T. Journal of Virology 1983 45(1):104-113

4. Wilhelmsen KC, Temin HM: Structure and dimorphism of c-rel (turkey), the cellular homolog to the oncogene of reticuloendotheliosis virus strain T. Journal of Virology 1984 49(2):521-529

5. Wilhelmsen KC, Chen IS, Temin HM. The organization of c-rel in chicken and turkey DNAS. Progress in Clinical and biological Research 1983 119:43-56

6. Wilhelmsen KC, Eggleton K, Temin HM: Nucleic acid sequence of the oncogene v-rel in reticuloendotheliosis virus strain T and its cellular homolog, the proto-oncogene c-rel. Journal of Virology 1984 52:172-182

7. Brzustowicz LM, Lehner T, Castilla LH, Penchaszadeh GK, Wilhelmsen KC, Daniels R, Davies KE, Leppert M, Ziter F, Wood D, Dubowitz V, Zerres K, Hausmanowa-Petrusewicz I, Ott J, Munsat TL, Gilliam TC: Genetic mapping of chronic childhood onset spinal muscular atrophy to chromosome 5q. Nature 1990 344:540-541

8. Wilhelmsen KC, Weeks DE, Nygaard TG, Moskowitz CB, Rosales RL, dela Paz DC, Sobrevega EE, Fahn S, Gilliam TC, Genetic mapping of "Lubag" (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentric region of the X chromosome. Annals of Neurology 1991 29(2):124-131

9. Kleyn PW, Brzustowicz LM, Wilhelmsen KC, Freimer NB, Miller JM, Munsat TL, Gilliam TC: Spinal muscular atrophy is not the result of mutations at the beta-hexoseminadase or GM2 activator loci. Neurology 1991 41(9):1418-1422

10. Lasser DM, Wilhelmsen KC, Nygaard TG, Tantravahi U. Characterization of microsatellite polymorphisms DXS691 and DXS692: genetic mapping to Xq26.2-Xq27 and Xq25-Xq26.2. Genomics 1993 16(3):785-786

11. Waters CH, Takahashi H, Wilhelmsen KC, Shubin R, Snow BJ, Nygaard TG, Moskowitz CB, Fahn S, and Calne DB. Phenotypic expression of X-linked dystonia-parkinsonism (Lubag) in two women. Neurology 1993 43(8):1555-1558

12. Eidelberg D, Takikawa S, Wilhelmsen KC, Dhawan V, Chaly T, Robeson W, Dahl R, Greene P, Hunt A, Przedborski S, and Fahn S. Positron emission tomography findings in Filipino X-linked dystonia-parkinsonism. Annals of Neurology 1993 34(2):185-191

13. Nygaard TG, Wilhelmsen KC, Risch NJ, Brown DL, Trugman JL, Gilliam TC, Fahn S. Weeks DE. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q. Nature Genetics 1993 5(4):386-391

14. Lasser DM, DeVivio DC, Garvin J, Wilhelmsen KC. Turcot's syndrome: evidence for linkage to the adenomatous polyposis coli (APC) locus. Neurology 1994 44(6):1083-1086

15. Lew MF, Shindo M, Moskowitz CB, Wilhelmsen KC, Fahn S, Waters CH. Adductor laryngeal breathing dystonia in a patient with lubag (X-linked dystonia-parkinsonism syndrome). Movement Disorders 1994 9(3):318-320

16. Kramer PL, Heiman GA, Gasser T, Ozelius LJ, de Leon D, Brin MF, Burke RE, Hewett J, Hunt AL, Moskowitz C, Nygaard TG, Wilhelmsen KC, Fahn S, Breakefield XO, Risch NJ and Bressman SB. The DYTI gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-Jews. American Journal of Human Genetics 1994 55:468-475

17. Lynch T, Sano M, Marder KS, Bell KL, Foster NL, Defendini RF, Sima AAF, Keohane C, Nygaard TG, Fahn S, Mayeux R, Rowland LP, Wilhelmsen KC. Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. Neurology 1994 44:1878-1884

18. Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG. Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22. American Journal of Human Genetics 1994 55(6):1159-1165

19. Bressman SB, Hunt AL, Heiman GA, Brin MF, Burke RE, Fahn S, Trugman JL, de Leon D, Kramer PL, Wilhelmsen KC and Nygaard TG. Exclusion of the DYT1 locus in a non-Jewish family with early-onset dystonia. Movement Disorders 1994 9(6):626-632

20. Weeks DE, Nygaard TG, Neystat M, Harby LD, and Wilhelmsen KC. A high resolution genetic linkage map of the pericentromeric region of the human X chromosome. Genomics 1995 26(1):39-46

21. Ottman R, Risch N, Hauser WA, Pedley TA, Lee JH, Baker-Cummings C, Lustenberger A, Nagle KJ, Lee KS, Scheur ML, Neystat M, Susser M, Wilhelmsen KC. Localization of a gene for partial epilepsy to chromosome 10q. Nature Genetics 1995 10:56-60

22. Wilhelmsen KC, Blake D, Lynch T, Mabutas J, De Vera M, Hirano M, Gilliam TC, Murphy P, Bonilla E, Schotland DL, Lovelace RE, Hays AP, and Rowland LP. Chromosome 12-linked autosomal dominant scapuloperoneal muscular dystrophy. Annals of Neurology 1996 39(4): 507-520

23. Petersen RB, Tabaton M, Chen SG, Monari L, Richardson SL, Lynch T, Manetto V, Lanska DJ, Markesbery WR, Currier RD, Autilio-Gambetti L, Wilhelmsen KC, Gambetti P. Familial progressive subcortical gliosis: presence of prions and linkage to chromosome 17. Neurology 1995 45:1063-1067

24. Sima AAF, Defendini RF, Keohane C, D’Amato C, Foster NL, Parchi P, Gambetti P, Lynch T, Wilhelmsen KC. The neuropathology of chromosome 17-linked dementia. Annals of Neurology 1996 39(6):734-743

25. Wijker M, Wszolek ZK, Wolters ECH, Rooimans MA, Pals G, Pfeiffer RF, Lynch T, Rodnitzsky RL, Wilhelmsen KC, Arwert F. Localization of the gene for rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration to chromosome 17q21. Human Molecular Genetics 1996 5(1):151-154

26. Isozumi K, DeLong R, Kaplan J, Deng H-X, Iqbal Z, Hung W-Y, Wilhelmsen KC, Hentati A, Pericak-Vance MA, and Siddique T. Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. Human Molecular Genetics 1996 5(9):1377-1382

27. Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 1997 95(12):2603-2606

28. Foster NL, Wilhelmsen KC, Sima AAF, Jones MZ, D’Amato C, Gilman S, and the Participants of the Chromosome 17-Related dementia Conference. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Annals of Neurology 1997 41(6):706-715

29. Wilhelmsen KC, Mirel D, Marder K, Bernstein M, Naini A, Leal SM, Cote LJ, Tang M-X, Freyer G, Graziano J, and Mayeux R. Is there a genetic susceptibility locus for Parkinson’s disease on chromosome 22q13? Annals of Neurology 1997 41(6):813-817

30. Wilhelmsen KC and Wszolek Z. Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration (PPND) and disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) are clinically distinct conditions that are both linked to 17q21-22. Parkinsonism and Related Disorders 1997 3(2):67-76

31. Ikeuchi T, Sanpei K, Takano H, Sasaki H, Tashiro K, Cancel G, Brice A, Bird TD, Schellenberg GD, Pericak-Vance MA, Welsh-Bohmer KA, Clark LN, Wilhelmsen KC and Tsuji S. A novel long and unstable CAG/CTG trinucleotide repeat on chromosome 17q. Genomics 1998 49:321-326

32. Lendon CL, Lynch T, Norton J, McKeel DW, Busfield F, Craddock N, Chakraverty S, Gopalakrishnan G, Shears SD, Grimmett W, Wilhelmsen KC, Hansen L, Jr, Morris JC, and Goate AM. Hereditary Dysphasic Disinhibition Dementia: A frontal-temporal dementia linked to 17q21-22. Neurology 1998 50:1546-1555

33. Mirel DB, Marder K, Graziano J, Freyer G, Zhao Q, Mayeux R, Wilhelmsen KC. Characterization of the human mitochondrial gene (ACO2). Gene 1998 213:205-218

34. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, D’Souza I, Lee VM.-Y. , Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related chromosome 17-linked neurodegenerative disorders. Proceedings of the National Academy of Sciences 1998 95:13103-13107

35. Jeppensen LL, Wilhelmsen K, Nielsen, LB, Jorgensen HS, Nakayama H, Raaschou HO, Nielsen JD, Olsen TS, Winther K. An insertion/deletion polymorphism in the promoter region of the plasminogen activator inhibitor-1 gene is associated with plasma levels but not with stroke risk in the elderly. Journal of Stroke and Cerebrovascular Diseases 1998 7(6):385-390

36. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BL, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VM-Y. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 1998 282(5395):1914-1917

37. Goedert M, Spillantini MG, Crowther RA, Chen SG, Parchi P, Tabaton M, Lanska DJ, Markesbery WR, Wilhelmsen KC, Dickson DW, Petersen RB, Gambetti P. Tau gene mutation in familial progressive subcortical gliosis. Nature Medicine 1999 5(4):454-457

38. Wilhelmsen KC, Clark LN, Miller BL, Geschwind DH. Tau Mutations in frontotemporal dementia. Proceedings of the 3rd International Conference on Frontotemporal Dementias, Dementia and Geriatric Cognitive Disorders 1999 10 Suppl 1:88-92

39. Nasreddine ZS, Loginov M, Clark LN, Lamarche J, Miller BL, Lamontagne A, Zhukareva V, Lee, VM-Y, Wilhelmsen KC, Geschwind DH. From genotype to phenotype: a clinical, pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation. Annals of Neurology 1999 45(6):704-715

40. Takacs Z, Wilhelmsen KC, Sorota S. Snake ?-neurotoxin binding site on the Egyptian cobra (Naja haje) nicotinic acetylcholine receptor is conserved. Mol Biol Evol 2001 18(9):1800-9

41. Geschwind DH, Robidoux J, Alarcon M, Miller BL, Wilhelmsen KC, Cummings JL, Nasreddine ZS. Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia. Ann Neurol 2001 50(6):741-6

42. Wilhelmsen KC, Forman MS, Rosen HJ, Alving L, Goldman J, Feiger J, Lee JV, Segall SK, Kramer JH, Lomen-Hoerth C, Rankin KP, Johnson J, Feiler HS, Weiner WM, Lee V M-Y, Trojanowski JQ, Miller BL, 17q Linked FTD-ALS Without Tau Mutations With Tau and a-Synuclein Inclusions. Submitted to Annals of Neurology

42. Wilhelmsen KC, Schuckit M, Smith TL, Lee JV, Segall SK, Feiler HS, Kalmijn J. The Search For Genes Related to a Low Level of Response to Alcohol Determined by Alcohol Challenge. Revision Submitted to Alcoholism: Clinical and Experimental Research

43. Swan GE, Hudmon KS, Cheng L, Jack JM, Hemberger K, Carmelli D, Khroyan TV, Huijun Z. Ring HZ, Hops H, Andrews JA, Tildesley E, McBride D, Benowitz N, Webster C, Wilhelmsen KC, Feiler H, Koenig B, Caron L, Illes J. Environmental and genetic determinants of tobacco use: A multidisciplinary, longitudinal family-based design. Revison Submitted to Cancer Epidemiology Biomarkers and Prevention. Note author order is based on institutional affiliation.

44. Vieten C, Seaton K, Feiler H, Wilhelmsen KC. The UCSF Family Alcoholism Study: I. Design, Methods, and Demographics. Anticipated Submission Date 3/18/03

45. Wilhelmsen KC, Ehlers CE, Heritability Analysis of Alcoholism and Substance Abuse in Mission Indians. Anticipated Submission date 3/25/03

46. Wilhelmsen KC, Ehlers CE. Evidence for Loci for Alcoholism Susceptibility in Mission Indians. Anticipated Submission date 3/30/03

47. Manuscript describing the positional cloning of the gene for Kindler’s syndrome for which my lab mapped the gene for Dr. Ervin Epstein at UCSF. Submission Date expected 3/16/03 to Nature Genetics. I don’t have the final title and authors.

48. Manuscript describing linkage for fever associated encephalopathy is in preparation by Mat Warmen from Case Western Reserve.

Manuscripts for linkage analysis for project described in 43,44 are also in preparation

Trainees

POSTDOCTORAL STUDENTS SUPERVISED:
1/93 – 6/95 Michael Neystat, Ph.D. Columbia University, New York
1/91 – 1/94 Tobjoern Nygaard, M.D. Columbia University, New York
6/93 – 6/95 Timothy Lynch, Ph.D. Columbia University, New York
7/95 – 1/00 Lorraine Clark, Ph.D. University of Manchester, U.K.
1/96 – 10/98 Katherine Dains, Ph.D. State University of New York, Stony Brook
11/95 - 10/96 Lise Jeppensen (Ph.D. cand.) University of Copenhagen, Denmark
6/95 – 10/98 Dan Mirel, Ph.D. University of California, Berkeley
9/98 – present Cassandra Vieten, Ph.D. California Institute of Integral Studies, S.F.
2/99 – 6/01 Barbara Kloeckener-Gruissem, Ph.D. University of Colorado, Boulder
2/99 – 2/01 Paul Hengen, Ph.D. Carleton University, Ottawa, Canada
3/99 – 6/00 Anthony Ashworth, Ph.D. Imperial College, London, England
12/99 – 1/01 Sietske Nora Heyn, Ph.D. University of California, Davis
6/00 – present Dina Phyere, Ph.D. University of California, Berkeley
3/02 – present Penelope Lind, Ph.D. University of Waikato, New Zealand

PRE-DOCTORAL STUDENTS SUPERVISED:
1/93 – 6/95 Zoltan Takacs Columbia University, New York

Contact Information

4109E Neuroscience Research Building, CB 7264
Chapel Hill, NC 27599-7264

Office: 919.966.1373
Lab: 919.966.2869
Fax: 919.966.3630 (fax)

Email: kirk_wilhelmsen<at>med.unc.edu

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