Candidate Genes for Tourette Syndrome

The genetics of Tourette Syndrome is complicated. TS is not "caused" by a single gene on a single chromosme. Rather, one inherits a susceptibility to developing Tourettes as a result of the compound effects of a large number of genes [Commings, Wu, et. al., 1996]. The more of these genes which a person has, the more susceptible that person is to developing TS. Having any (or all) of these genes does not guarantee that one will develop TS; not having any will not ensure not getting TS. Besides genetics, there are other environmental factors which can also lead to TS. One such environmental factor is the development of antibodies against certain proteins in the basal ganglia (an organ in the brain). These antibodies bear a striking similarity to antibodies against the streptococcus-A bacteria; for some reason, a majority of the TS sufferers who have been examined have these antibodies while a majority of the general population do not [Kurlan, 1998; Singer, 1998]. There is also the fact that males are much more likely than females to develop tics; while it is widely believed that the cause is hormonal, a clear link has not been established.

Genetics of TS and the ABO Blood Type. The ABO blood gene is on gene 9 at 9q34; So is dopamine beta hydroxylase, which is implicated in TS. A map of the human genome with putative TS genes is indicated in the following table. There is no indication that blood type is associated with TS but the DBH gene which has been associated with TS is in the same location as the ABO blood type gene

Researchers have identified many genes as candidates for TS. Some of the genes whose additive effects are probably involved in TS include those in the following list:

Protein	Gene Location	References
D2S1790	2 centromere	Simonec (1998)
DAT1	5p15.3	Vandenbergh (1992); Comings (1996); Wu (1998)
DRD1	5q35.1	Grandy and others 1990; Comings (1997)
D6S477	6p (distal)	Simonec (1998)
D8S257	8q	Simonec (1998)
ABO	9q34	Bennett and others 1995
DBH	9q34	Cummings(1996); Craig(1988); Sherrington (1995)
DRD2	11q22-23	Grandy (1989); Comings (1996,1997)
D14S1003	14q (proximal)	Simonec (1998)
D20S1085	20q (distal)	Simonec (1998)
D21S1252	21q	Simonec (1998)
TDO2	4q31	Comings (1995, 1996)
5HT1A	5q13	Jenner (1990); Lam (1996)
MAOA	Xp11.3	Harris (1993); Gade (1998)
CT	7 & 8	Boghosian-Sell (1996)

ABO = Blood type DAT1 = Dopamine Transporter 1
CT = Chromosomal Translocation
DBH = Dopamine Beta Hydroxylase
DRD1 = Dopamine Receptor D1 Subtype
MAOA = Monoamine Oxidase A
5HT1A = Seretonin (5-hydroxy tryptamine) Receptor 1A Subtype
TDO2 = Tryptophan 2,3-dioxygenase

Do your own literature search!

References

Bennett EP, Steffensen R, Clausen H, Weghuis DO, van Kessel AG (1995) Genomic cloning of the human histo-blood group ABO locus. Biochem Biophys Res Commun 1995 Jan 5;206(1):318-25

Boghosian-Sell, L., D.E. Comings, and J. Overhauser. "Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3." American Journal Of Human Genetics 59, no. 5 (1996): 999-1005.

Comings, D.E., R. Gade, D. Muhleman, C. Chiu, S. Wu, M. To, M. Spence, G. Dietz, E. Winn-Deen, R.J. Rosenthal, H.R. Lesieur, L. Rugle, J. Sverd, L. Ferry, J.P. Johnson, and J.P. MacMurray. "Exon and intron variants in the human tryptophan 2,3-dioxygenase gene: potential association with Tourette syndrome, substance abuse and other disorders." Pharmacogenetics 6, no. 4 (1996): 307-18.

Comings,D.E., Muhleman,D., Dietz,G., Sherman,M. and Forest,G.L. (1995) Sequence of human tryptophan 2,3-dioxygenase (TDO2): presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat Genomics 29 (2), 390-396 (1995)

Comings, D.E., S. Wu, C. Chiu, R.H. Ring, R. Gade, C. Ahn, J.P. MacMurray, G. Dietz, and D. Muhleman. "Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes--DRD2, D beta H, and DAT1." American Journal Of Medical Genetics 67, no. 3 (1996): 264-88.

Comings, D.E., R. Gade, S. Wu, C. Chiu, G. Dietz, D. Muhleman, G. Saucier, L. Ferry, R.J. Rosenthal, H.R. Lesieur, L.J. Rugle, and P. MacMurray. "Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors." Molecular Psychiatry 2, no. 1 (1997): 44-56.

Craig SP, Buckle VJ, Lamouroux A, Mallet J, Craig IW (1988) Localization of the human dopamine beta hydroxylase (DBH) gene to chromosome 9q34. Cytogenet Cell Genet 1988;48(1):48-50

Gade, R., D. Muhleman, H. Blake, J. MacMurray, P. Johnson, R. Verde, G. Saucier, and D.E. Comings. "Correlation of length of VNTR alleles at the X-linked MAOA gene and phenotypic effect in Tourette syndrome and drug abuse." Molecular Psychiatry 3, no. 1 (1998): 50-60.

Grandy DK, Litt M, Allen L, Bunzow JR, Marchionni M, Makam H, Reed L, Magenis RE, Civelli O (1989) The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. Am J Hum Genet 1989 Nov;45(5):778-85

Grandy DK, Zhou QY, Allen L, Litt R, Magenis RE, Civelli O, Litt M (1990) A human D1 dopamine receptor gene is located on chromosome 5 at q35.1 and identifies an EcoRI RFLP. Am J Hum Genet 1990 Nov;47(5):828-34

Harris BD, Kurth JH, Barnes RI, Bowcock AM, Kurth MC (1993) Linkage analysis of the monoamine A and B genes using newly-defined polymorphisms. Cytogenet Cell Genet 1993;62(4):236-7

Jenner DE (1990) NIH Gene bank Accession Number X53826 http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=X53826&form=6&db=s&Dopt=g

Kurlan, R. "Tourette's syndrome and 'PANDAS': will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection [see comments]." Neurology 50, no. 6 (1998): 1530-4.

Lam, S., Y. Shen, T. Nguyen, T.L. Messier, M. Brann, D. Comings, S.R. George, and B.F. O'Dowd. "A serotonin receptor gene (5HT1A) variant found in a Tourette's syndrome patient." Biochemical And Biophysical Research Communications 219, no. 3 (1996): 853-8.

Rowe, D.C., C. Stever, J.M. Gard, H.H. Cleveland, M.L. Sanders, A. Abramowitz, S.T. Kozol, J.H. Mohr, S.L. Sherman, and I.D. Waldman. "The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children." Behavior Genetics 28, no. 3 (1998): 215-25.

Sherrington R, Curtis D, Brynjolfsson J, Moloney E, Rifkin L, Petursson H, Gurling H A linkage study of affective disorder with DNA markers for the ABO-AK1-ORM linkage group near the dopamine beta hydroxylase gene. Biol Psychiatry 1994 Oct 1;36(7):434-42

Simonic, I., G.S. Gericke, J. Ott, and J.L. Weber. "Identification of genetic markers associated with Gilles de la Tourette syndrome in an Afrikaner population." American Journal Of Human Genetics 63, no. 3 (1998): 839-46.

Singer, H.S., J.D. Giuliano, B.H. Hansen, J.J. Hallett, J.P. Laurino, M. Benson, and L.S. Kiessling. "Antibodies against human putamen in children with Tourette syndrome [see comments]." Neurology 50, no. 6 (1998): 1618-24.

Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR (1992) Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 1992 Dec;14(4):1104-6