ORIGINAL ARTICLES No Coding Variant of the Tryptophan Hydroxylase Gene Detected in Seasonal Affective Disorder, Obsessive–Compulsive Disorder, Anorexia Nervosa, and Alcoholism Ling Han, David A. Nielsen, Norman E. Rosenthal, Kimberly Jefferson, Walter Kaye, Dennis Murphy, Marti Altemus, Julie Humphries, Giovanni Cassano, Alessandro Rotondo, Matti Virkkunen, Markku Linnoila, and David Goldman Background: The goal of this study was to evaluate the role of genetic variation in the coding sequence of tryp- tophan hydroxylase (TPH) in the pathogenesis of several psychiatric diseases in which altered serotonin function has been implicated: bipolar affective disorder (BP), obsessive– compulsive disorder (OCD), anorexia nervosa (AN), seasonal affective disorder (SAD), panic disorder (PD), and alcoholism (Alc). Methods: Ninety-three percent of the TPH coding se- quence was screened by polymerase chain reaction single- strand conformation polymorphism (SSCP) for DNA se- quence variations in 128 AN, 88 OCD, 72 SAD, 45 PD, and 36 BP patients and 142 normal volunteers. Also included in the screening were 61 Alc randomly selected from a Finnish alcoholic population in which an associ- ation of a TPH intron 7 polymorphism with suicidality was previously observed. Polymorphisms detected by SSCP were characterized by DNA sequencing and by allele- specific restriction enzyme digestion. Genotyping was then performed in 34 Finnish alcoholic suicide attempters. Results: A rare silent mutation was identified in exon 10 and is designated T1095C. The C1095 allele was found in 1 OCD and in 2 AN subjects; all 3 individuals were heterozygous (C1095/T1095) for the variant allele. No association was observed between this TPH T1095C variant with either OCD, AN, Alc, or suicidality. Conclusion: These results suggest that the coding se- quence of the TPH gene does not contain abundant variants, and may not play a major role in vulnerability to several psychopathologies in which reduced serotonin turnover has been implicated. Biol Psychiatry 1999;45: 615– 619 © 1999 Society of Biological Psychiatry Key Words: Anorexia nervosa, obsessive– compulsive disorder, tryptophan hydroxylase gene, polymorphism, single-strand conformation polymorphism Introduction S everal lines of evidence indicate that central seroto- nergic neurotransmission may be reduced in certain psychiatric diseases that are characterized by a deficit in impulse control (Coccaro and Murphy 1990; Asberg et al 1976; Van Praag et al 1970; Roy et al 1986; Virkkunen et al 1989; Linnoila et al 1983; Ballenger et al 1979). These disorders include depressive disorders, suicidality, alco- holism (Alc), obsessive– compulsive disorder (OCD), an- orexia nervosa (AN), bipolar affective disorder (BP), and panic disorder (PD). Accumulating data from twin, family, and adoption studies also indicate that most of these disorders have a genetic component (Gershon and Clon- inger 1994). Since tryptophan hydroxylase (TPH) is the rate limiting enzyme in the pathway of serotonin synthesis, it may play a vital role in interindividual variation in serotonin metab- olism. Previous studies have implicated TPH in impulse control. When a TPH intron 7 polymorphism was evalu- ated in a cohort of Finnish alcohol offenders, a significant association between this TPH marker and suicidality was observed (Nielsen et al 1994). These findings were re- cently replicated in a second clinical population from Finland (Nielsen et al 1998). In a separate study that used an undefined French population sample and an unpub- lished TPH polymorphism, Abbar et al (1995) found no association between TPH and suicidality. If the TPH/suicidality association is valid, the intron 7 polymorphism either alters the expression or structure of the gene product, or is linked to a variant that does. Such a variant could be found in either the coding region or the noncoding region of the TPH gene. In this study, we have From the NIAAA/Lab of Neurogenetics, National Institutes of Health, Rockville, Maryland. Address reprint requests to David Goldman, MD, National Institutes of Health, NIAAA/Lab of Neurogenetics, 12420 Parklawn Drive, Park 5 Bldg, Rm 451, MSC 8110, Rockville, MD 20851. Received May 13, 1997; revised November 6, 1997; accepted February 16, 1998. © 1999 Society of Biological Psychiatry 0006-3223/99/$19.00 PII S0006-3223(98)00122-X