憂鬱症、焦慮症與其共病形式之間的關聯及其背後的病因在心理社會角度已被廣泛的研究。而在生物病因方面，以腦影像學、神經內分泌學為主導的研究也有豐碩的成果。在過去的家族及雙生子研究發現，遺傳在憂鬱症、焦慮症以及其共病的病因上扮演相當重要的角色，但是利用基因連鎖定位研究的結果卻不一，這可能是因為以上疾病乃是多基因共同決定的複雜疾病，因此若要尋找其有關的致病基因，需要更精確快速的方法來進行研究。血清素系統調控許多生理功能並與情緒、危急反應有關，在精神疾病的病因上可能佔有重要的地位，因而與此系統相關的基因已廣泛的挑選來作為精神疾病研究的候選基因。人類色胺酸氫氧基化脢基因是合成血清素的速率決定脢，位在染色體11p15.3-14的位置，過去針對此一基因的精神疾病病因學研究多半僅限於位於第七個非表現序列的A20004C標竿，為更精確的釐清此基因與疾病的關係，在其序列內挑選可能具有功能且數量較多、較密集的標竿來進行相關研究是必要的。單一核甘酸多型性在基因組中是數量最多的序列多型性形式，因為其一般只有兩種對偶基因的改變，較容易利用來建立自動化分析的過程，且位在基因中不同位置的單一核甘酸多型性對基因的表現、蛋白質產物的功能往往也具有決定性的地位。為更深入瞭解，本研究針對206名台灣地區產後婦女，分為憂鬱、焦慮、共病及正常組別，在色胺酸氫氧基化脢基因挑選了五個單一核甘酸多型性標竿來進行研究，希望藉此瞭解此基因在上述疾病的病因學上所扮演的角色，並使用兩種快速的基因型鑑定方法來鑑別基因型，基因型鑑定的結果使用卡方檢定來比較憂鬱、焦慮、憂鬱焦慮共病與正常對照組之間的差異。分析結果指出，所挑選的五個標竿與在各組之間沒有明顯差異。因此本研究結果推測色胺酸氫氧基化脢基因在台灣地區憂鬱與焦慮疾病的病因上可能不具有決定性的角色。但其對此類疾病是否有極微小的影響或調控，則需要進一步的釐清。

Depression and anxiety disorders are widely studied in the psychological aspects. Previous family twin studies had suggested that genetic basis plays an important role in depression and anxiety disorders. But in linkage studies, the findings are not consistent. Serotonin is the biogenic amine neurotransmitter most commonly associated with depression and anxiety. The human tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis, thus it has been a candidate gene for genetic research with various psychiatric disorders. SNPs are major contributors to genetic variation and mutationally more stable, making them suitable for association studies in which linkage disequilibrium (LD) between markers and an unknown variant is used to map disease-causing mutations. The aim of this study is to examine if major depression, anxiety disorders and comorbid depression and anxiety is related to genetic variations in human TPH gene. In this study, 206 females from a postpartum depression study, which were classified into depression, anxiety, comorbid anxiety and depression, and normal control, were also collected. Five SNP markers within and around TPH gene were genotyped using two fast and convenient genotyping methods. Genotyping results were analyzed with chi-square analysis to examine to association between groups. Result of this study suggested that TPH may not play an important role in the etiology of depression, anxiety and comorbid depression and anxiety in our population. However, further study may be required to investigate if TPH has minor regulatory effect in the pathogenesis of these psychiatric disorders.

Allen, M. G., Cohen, S., Pollin, W., & Greenspan, S. I. (1974). Affective illness in veteran twins: A diagnostic review. American Journal of Psychiatry, 131, 1234-1239.
Andrews, G., Stewart, G., Allen, R., & Henderson, A. S. (1990). The genetics of six neurotic disorders: a twin study. J Affect Disord, 19, 23-29.
Diagnostic and Statistical Manual of Mental Disorders, (1994).
Bellivier, F., Leboyer, M., Courtet, P., Buresi, C., Beaufils, B., Samolyk, D., et al. (1998). Association between the tryptophan hydroxylase gene and manic-depressive illness. Arch Gen Psychiatry, 55, 33-37.
Bertelsen, A., Harvald, B., & Hauge, M. A. (1977). A Danish twin study of manic-depressive disorders. British Journal of Psychiatry, 130, 330-351.
Black, D. W., Noyes, R., Jr., Goldstein, R. B., & Blum, N. (1992). A family study of obsessive-compulsive disorder. Arch Gen Psychiatry, 49, 362-368.
Boyd, J. H., Burke, J. D., Jr., Gruenberg, E., Holzer, C. E., 3rd, Rae, D. S., George, L. K., et al. (1984). Exclusion criteria of DSM-III. A study of co-occurrence of hierarchy-free syndromes. Arch Gen Psychiatry, 41, 983-989.
Brookes, A. J. (1999). The essence of SNPs. Gene, 234, 177-186.
Burmeister, M. (1999). Basic concepts in the study of diseases with complex genetics. Biol. Psychiatry, 45, 522-532.
Cardon, L. R., & Bell, J. I. (2001). Association study designs for complex diseases. Nat Rev Genet, 2, 91-99.
Carlson, N. R. (2001). Physiology of behavior (7th ed.). Boston ; London: Allyn and Bacon.
Chard, T., & Lilford, R. J. (1995). Basic sciences for obstetrics and gynaecology (4th ed.). London: Springer-Verlag.
Charney, D. S., Nestler, E. J., & Bunney, B. S. (1999). Neurobiology of mental illness. New York; Oxford: Oxford University Press.
Clark, L. A., Watson, D., & Mineka, S. (1994). Temperament, personality, and the mood and anxiety disorders. J Abnorm Psychol, 103, 103-116.
Cooper, P. J., & Murray, L. (1998). Postnatal depression. Bmj, 316, 1884-1886.
Craig, S. P., Boularand, S., Darmon, M. C., Mallet, J., & Craig, I. W. (1991). Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3-p14 by in situ hybridization. Cytogenet Cell Genet, 56, 157-159.
Delgado, P. L. (2000). Depression: the case for a monoamine deficiency. J Clin Psychiatry, 61 Suppl 6, 7-11.
Du, L., Bakish, D., & Hrdina, P. D. (2001). Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder. J Affect Disord, 65, 37-44.
Eaton, W. W., Kessler, R. C., Wittchen, H. U., & Magee, W. J. (1994). Panic and panic disorder in the United States. Am J Psychiatry, 151, 413-420.
Fehr, C., Schleicher, A., Szegedi, A., Anghelescu, I., Klawe, C., Hiemke, C., et al. (2001). Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy. Prog Neuropsychopharmacol Biol Psychiatry, 25, 965-982.
Feighner, J. P., & Boyer, W. F. (1991). Selective serotonin re-uptake inhibitors : the clinical use of citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Chichester: Wiley.
Feinstein. (1970). The pre-therapeutic classification of comorbidity in chronic disease. Journal of Chronic Disease, 23, 455-468.
Frisch, A., Michaelovsky, E., Rockah, R., Amir, I., Hermesh, H., Laor, N., et al. (2000). Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways. Eur Neuropsychopharmacol, 10, 205-209.
Fulop, G., Strain, J. J., Vita, J., Lyons, J. S., & Hammer, J. S. (1987). Impact of psychiatric comorbidity on length of hospital stay for medical/surgical patients: a preliminary report. Am J Psychiatry, 144, 878-882.
Gershon, E. S., Hamovit, J. H., Guroff, J. J., Dibble, E., Leckman, J. F., Sceery, W., et al. (1982). A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Archives of General Psychiatry, 39, 1157-1167.
Gershon, E. S., Mark, A., Cohen, N., Belizon, N., Baron, M., & Knobe, K. E. (1975). Transmitted factors in the morbid risk of affective disorders: A controlled study. Journal of Psychiatric Research, 12, 283-299.
Graeff, F. G., Guimaraes, F. S., De Andrade, T. G., & Deakin, J. F. (1996). Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav, 54, 129-141.
Gratacos, M., Nadal, M., Martin-Santos, R., Pujana, M. A., Gago, J., Peral, B., et al. (2001). A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell, 106, 367-379.
Hagnell, O., Lanke, J., & Rorsman, B. (1982). Suicide and depression in the male part of the Lundby study. Changes over time during a 25-year observation period. Neuropsychobiology, 8, 182-187.
Heim, C., & Nemeroff, C. B. (2001). The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry, 49, 1023-1039.
Helgason, T. (1979). Epidemiological investigations concerning affective disorders. In: Schou, M. and Stromgren, E. eds: Origin, Prevention, and Treatment of Affective Disorders. New York: Academic Press, 241-255.
Henegariu, O., Heerema, N. A., Dlouhy, S. R., Vance, G. H., & Vogt, P. H. (1997). Multiplex PCR: critical parameters and step-by-step protocol. Biotechniques, 23, 504-511.
Heninger, G. R., Delgado, P. L., & Charney, D. S. (1996). The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry, 29, 2-11.
Jardine, R., Martin, N. G., & Henderson, A. S. (1984). Genetic covariation between neuroticism and the symptoms of anxiety and depression. Genet Epidemiol, 1, 89-107.
Johnson, M. R., & Lydiard, R. B. (1995). The neurobiology of anxiety disorders. Psychiatr Clin North Am, 18, 681-725.
Kandel, E. R., Schwartz, J. H., & Jessell, T. M. (2000). Principles of neural science (4th ed.). New York, NY ; London: McGraw-Hill.
Kaplan, H. I., & Sadock, B. J. (1998). Kaplan & Sadock's synopsis of psychiatry :behavioral sciences/clinical psychiatry (8th ed. ed.). Baltimore ; London: Williams & Wilkins.
Kaplan, M. H., & Feinstein, A. R. (1974). The importance of classifying initial co-morbidity in evaluatin the outcome of diabetes mellitus. J Chronic Dis, 27, 387-404.
Karno, M., Golding, J. M., Sorenson, S. B., & Burnam, M. A. (1988). The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry, 45, 1094-1099.
Kathol, R. G. (1985). Etiologic implications of corticosteroid changes in affective disorder. Psychiatr Med, 3, 135-162.
Kathol, R. G., Jaeckle, R. S., Lopez, J. F., & Meller, W. H. (1989). Pathophysiology of HPA axis abnormalities in patients with major depression: an update. Am J Psychiatry, 146, 311-317.
Kendler, K. S. (1996). Major depression and generalised anxiety disorder. Same genes, (partly)different environments--revisited. Br J Psychiatry Suppl, 68-75.
Kendler, K. S., Heath, A. C., Martin, N. G., & Eaves, L. J. (1987). Symptoms of anxiety and symptoms of depression. Same genes, different environments? Arch Gen Psychiatry, 44, 451-457.
Kendler, K. S., Neale, M. C., Kessler, R. C., Heath, A. C., & Eaves, L. J. (1992). The genetic epidemiology of phobias in women. The interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia. Arch Gen Psychiatry, 49, 273-281.
Kendler, K. S., Neale, M. C., Kessler, R. C., Heath, A. C., & Eaves, L. J. (1993). A longitudinal twin study of personality and major depression in women. Arch Gen Psychiatry, 50, 853-862.
Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., et al. (1994). Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Archives of General Psychiatry, 51, 8-19.
Kunugi, H., Tatsumi, M., Sakai, T., Hattori, M., & Nanko, S. (1996). Serotonin transporter gene polymorphism and affective disorder. Lancet, 347, 1340.
Lai, T. J., Wu, C. Y., Fann, C. S. J., Chen, T. M., & Sun, H. S. (2002). Association Study of the Tryptophan Hydroxylase Gene Polymorephism and Bipolar Affective Disorder in Taiwan. Journal of Genetics and Molecular Biology (Taiwan), 13, 101-104.
Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., et al. (2001). Initial sequencing and analysis of the human genome. Nature, 409, 860-921.
Leckman, J. F., Weissman, M. M., Merikangas, K. R., Pauls, D. L., & Prusoff, B. A. (1983). Panic disorder and major depression. Increased risk of depression, alcoholism, panic, and phobic disorders in families of depressed probands with panic disorder. Arch Gen Psychiatry, 40, 1055-1060.
Lewontin, R. C. (1964). The interaction of selection and linkage. I. General considerations: heterotic models. Genetics, 49, 49-67.
Llewellyn, A. M., Stowe, Z. N., & Nemeroff, C. B. (1997). Depression during pregnancy and the puerperium. J Clin Psychiatry, 58 Suppl 15, 26-32.
Manji, H. K., Drevets, W. C., & Charney, D. S. (2001). The cellular neurobiology of depression. Nat Med, 7, 541-547.
Manki, H., Kanba, S., Muramatsu, T., Higuchi, S., Suzuki, E., Matsushita, S., et al. (1996). Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders. Journal of Affective Disorders, 40, 7-13.
Mann, J. J., Malone, K. M., Nielsen, D. A., Goldman, D., Erdos, J., & Gelernter, J. (1997). Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry, 154, 1451-1453.
Manuck, S. B., Flory, J. D., Ferrell, R. E., Dent, K. M., Mann, J. J., & Muldoon, M. F. (1999). Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene. Biol Psychiatry, 45, 603-614.
Maser, J. D., & Cloninger, C. R. (1990). Comorbidity of mood and anxiety disorders. Washington: American Psychiatric Press.
McGuffin, P., Katz, R., Watkins, S., & Rutherford, J. (1996). A hospital-based twin register of the heritability of DSM-IV unipolar depression. Archives of General Psychiatry, 53, 129-136.
Metz, A., Sichel, D. A., & Goff, D. C. (1988). Postpartum panic disorder. J Clin Psychiatry, 49, 278-279.
Moldin, S. O., Reich, T., & and Rice, J. P. (1991). Current perspectives on the genetics of unipolar depression. Behavior Genetics, 21, 211-242.
Murakami, F., Shimomura, T., Kotani, K., Ikawa, S., Nanba, E., & Adachi, K. (1999). Anxiety traits associated with a polymorphism in the serotonin transporter gene regulatory region in the Japanese. J Hum Genet, 44, 15-17.
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002). Neurobiology of depression. Neuron, 34, 13-25.
New, A. S., Gelernter, J., Yovell, Y., Trestman, R. L., Nielsen, D. A., Silverman, J., et al. (1998). Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study. Am J Med Genet, 81, 13-17.
Nielsen, D. A., Goldman, D., Virkkunen, M., Tokola, R., Rawlings, R., & Linnoila, M. (1994). Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen Psychiatry, 51, 34-38.
Nielsen, D. A., Virkkunen, M., Lappalainen, J., Eggert, M., Brown, G. L., Long, J. C., et al. (1998). A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch Gen Psychiatry, 55, 593-602.
Ninan, P. T. (1999). The functional anatomy, neurochemistry, and pharmacology of anxiety. J Clin Psychiatry, 60 Suppl 22, 12-17.
Nolan, K. A., Volavka, J., Lachman, H. M., & Saito, T. (2000). An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder. Psychiatr Genet, 10, 109-115.
Nordborg, M., & Tavare, S. (2002). Linkage disequilibrium: what history has to tell us. Trends Genet, 18, 83-90.
Ogilvie, A. D., Battersby, S., Bubb, V. J., Fink, G., Harmar, A. J., Goodwin, G. M., et al. (1996). Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet, 347, 731-733.
Osher, Y., Hamer, D., & Benjamin, J. (2000). Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs. Mol Psychiatry, 5, 216-219.
Pauls, D. L., Leckman, J. F., & Cohen, D. J. (1994). Evidence against a genetic relationship between Tourette's syndrome and anxiety, depression, panic and phobic disorders. Br J Psychiatry, 164, 215-221.
Reich, D. E., Cargill, M., Bolk, S., Ireland, J., Sabeti, P. C., Richter, D. J., et al. (2001). Linkage disequilibrium in the human genome. Nature, 411, 199-204.
Risch, N. J. (2000). Searching for genetic determinants in the new millennium. Nature, 405, 847-856.
Rosen, J. B., & Schulkin, J. (1998). From normal fear to pathological anxiety. Psychol Rev, 105, 325-350.
Sobel, E., & Lange, K. (1996). Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet, 58, 1323-1337.
Stahl, S. M. (2000). Essential psychopharmacology : neuroscientific basis and practical applications (2nd ed.). Cambridge: Cambridge University Press.
Stober, G., Heils, A., & Lesch, K. P. (1996). Serotonin transporter gene polymorphism and affective disorder. Lancet, 347, 1340-1341.
Sturt, E., Kumakura, N., & Der, G. (1984). How depressing life is - life-long morbidity risk for depressive disorder in the general population. Journal of Affective Disorders, 7, 109-122.
Thorgeirsson, T. E., Oskarsson, H., Desnica, N., Kostic, J. P., Stefansson, J. G., Kolbeinsson, H., et al. (2003). Anxiety with panic disorder linked to chromosome 9q in Iceland. Am J Hum Genet, 72, 1221-1230.
Torgersen, S. (1986). Genetic factors in moderately severe and mild affective disorders. . Archives of General Psychiatry, 43, 222-226.
Vaidya, V. A. (2000). Stress, depression and hippocampal damage. J Biosci, 25, 123-124.
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., et al. (2001). The sequence of the human genome. Science, 291, 1304-1351.
Virkkunen, M., Goldman, D., Nielsen, D. A., & Linnoila, M. (1995). Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence. J Psychiatry Neurosci, 20, 271-275.
Walther, D. J., Peter, J. U., Bashammakh, S., Hortnagl, H., Voits, M., Fink, H., et al. (2003). Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science, 299, 76.
Weissman, M. M., Gershon, E. S., Kidd, K. K., Prusoff, B. A., Leckman, J. F., Dibble, E., et al. (1984). Psychiatric disorders in the relatives of probands with affective disorders. Archives of General Psychiatry, 41, 13-21.
Winokur, G., Tsuang, M. T., & Crowe, R. R. (1982). The Iowa 500: Affective disorder in relatives of manic and depressive patients. American Journal of Psychiatry, 139, 209-212.
Ye, S., Dhillon, S., Ke, X., Collins, A. R., & Day, I. N. (2001). An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res, 29, E88-88.
Yeh, F. C., R. Yang, Boyle, T. J., Z.Ye, & Xiyan., J. M. (2000). PopGene32, Microsoft Windows-based freeware for population genetic analysis. (Version 1.32). Edmonton, Canada: Molecular Biology and Biotechnology Centre, University of Alberta.