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Original Article |

A Tryptophan Hydroxylase Gene Marker for Suicidality and Alcoholism FREE

David A. Nielsen, PhD; Matti Virkkunen, MD; Jaakko Lappalainen, MD; Monica Eggert, MD; Gerald L. Brown, MD; Jeffrey C. Long, PhD; David Goldman, MD; Markku Linnoila, MD, PhD
[+] Author Affiliations

From the Section of Molecular Genetics (Dr Nielsen), Laboratory of Neurogenetics (Drs Lappalainen, Long, and Goldman), and Division of Intramural Clinical and Biologic Research (Drs Brown and Linnoila), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Md; and the Department of Psychiatry, University of Helsinki, Helsinki, Finland (Drs Virkkunen and Eggert). Dr Linnoila is deceased.


Arch Gen Psychiatry. 1998;55(7):593-602. doi:10.1001/archpsyc.55.7.593.
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Published online

Background  Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Low turnover rate of this monoamine neurotransmitter is associated with impaired impulse control. We previously reported that, in Finns, TPH genotype was associated with suicidality, a pathophysiological mechanism that may involve impaired impulse control.

Methods  Association and sib-pair linkage analyses of a polymorphism in intron 7 of the TPH gene with suicidality, alcoholism, and the Karolinska Scales of Personality were conducted in 804 Finnish alcoholic offenders, controls, and their relatives, in a sample that included 369 sib pairs.

Results  The association of the TPH I7779C (L) allele to suicidality in impulsive offenders reported previously was replicated in a new group of Finnish offenders (P=.001, n=122). The intron 7 variant in the TPH gene showed significant evidence for linkage to suicidality (P=.006 in unaffected sib pairs), severe suicide attempts (P=.006 in unaffected sib pairs; regression: P=.01), alcoholism (P=.003 in unaffected sib-pairs; regression: P=.02), and Karolinska Scales of Personality socialization score (regression: P=.002).

Conclusions  The status of the TPH A779C allele as a marker for suicidality was replicated and linkage with alcoholism and Karolinska Scales of Personality socialization score was also observed. A functional variant(s) in or close to the TPH gene may predispose individuals to suicidality and other behaviors thought to be influenced by serotonin.

FAMILY, ADOPTION, and twin studies have demonstrated heritability and familial transmission of suicidality1,2 and alcoholism.35 In fact, suicidality and alcoholism may share common genetic vulnerability variables. A major risk factor for suicidality is alcoholism. Compared with the general population, alcoholism increases the risk of suicide 60- to 120-fold when comorbid with a mental disorder.6 Furthermore, alcoholism is diagnosed ante mortem in 25% of suicide victims.7

Low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations have been detected in patients with suicidal behavior1,811 and early-onset alcoholism,12,13 indicating a lower rate of serotonin turnover. Genetic variation may play a role in the control of serotonin turnover rate.14 Many genes involved in serotonin metabolism have allelic variants including monoamine oxidase A,15 tryptophan hydroxylase (TPH),16 cyclohydrolase,17 the serotonin transporter,18,19 and the serotonin 5-HT1A,2022 5-HT1Da,23 5-HT1Dβ,24,25 5-HT1F,26 5-HT2A,27,28 5-HT2C,29 and 5-HT730 receptors.

Several serotonergic variants alter the expression or the properties of the gene product and may modify behavior. A 5-HT1A variant lowers agonist-mediated receptor down-regulation rate and desensitization,21 and a 5-HT2A variant diminishes serotonin-mediated intracellular calcium release.27 In 1 kindred, a monoamine oxidase A variant produced a truncated protein that led to an X-linked syndrome characterized by increased impulsive behavior.15 A serotonin transporter promoter variant attenuates transcription and accounts partially for the variance in anxiety-related personality traits.18 These findings, like most in psychiatric genetics, remain unreplicated or uncertain.

Inherited variants of TPH, the rate-limiting enzyme in serotonin biosynthesis in the neurons of the raphe nuclei,31 could influence serotonin metabolism in the brain. We previously observed associations of a TPH intron 7 variant to suicidality and CSF 5-HIAA concentrations among Finnish impulsive offenders.32 Both suicidality and a lifetime history of multiple suicide attempts were associated with TPH genotype. The TPH intron 7 variant is an A-to-C transversion at nucleotide 779 of intron 7.33 Although the variant was found in the polypyrimidine stretch preceding the 3‘ acceptor splice site, no alteration in splicing was identified when complementary DNAs from both alleles were sequenced.33 It is hypothesized that the I7 A779C polymorphism could be a marker for a nearby, unidentified functional variant(s).

Two other polymorphic nucleotides in the TPH gene have been reported. An A-to-C transversion at nucleotide 218 of intron 7 is in tight disequilibrium with the A779C polymorphism.33 Another TPH variant has been reported by Abbar et al34; however, the nature and location of this AvaII restriction fragment length polymorphism remains unpublished.

Although alcoholism and suicidality represent complex phenotypes, it may be possible to identify genetic variants that have quantitative influences on these behaviors. Toward this goal, we investigated the role of TPH in predisposing individuals to suicidality, alcoholism, and the development of personality traits in a large Finnish cohort. Using association and linkage analyses, we replicated the previous association of a TPH genetic marker to suicidality and extend this finding to related behavioral phenotypes.

SUBJECTS

The Finnish sample consisted of 268 male alcoholic violent offenders and fire setters who were ordered to undergo forensic psychiatric examination by a district court, 256 controls, 274 relatives of violent offenders, and 6 relatives of controls (Table 1). The controls were chosen to roughly match the patients for age, sex, and social class. All controls were recruited by advertisements placed in trade schools, in police and fire stations, and on the docks in Helsinki. The violent offenders and fire setters were classified as impulsive (n=168) or nonimpulsive (n=87) on the basis of the characteristics of the crime for which they were remanded to the forensic psychiatric examination. Crimes classified as impulsive were unpremeditated and unprovoked, whereas those classified as nonimpulsive were clearly premeditated.35 The classification was made by one of us (M.V.), blind to the biochemical and genetic data, by analysis of the police records, which included interviews of the offender and witnesses to the index crime. All subjects were asked to participate in the study by a physician who was not an investigator. All signed a written informed consent. The study was approved by the National Institute of Mental Health Intramural Research Program Institutional Review Board and the Office of Protection From Research Risks, Bethesda, Md, in the United States and by the University of Helsinki Central Hospital and Department of Psychiatry Institutional Review Boards in Finland.

Table Graphic Jump LocationTable 1. Demographics of the Finnish Subjects*
PSYCHIATRIC DIAGNOSIS

A total of 192 violent offenders, 219 controls, and 269 relatives of controls were interviewed by a research psychiatrist (M.E.) using the Structured Clinical Interview for DSM-III-R.36 The interviews were independently blind-rated for DSM-III-R diagnoses by 2 research psychiatrists. Discrepancies were resolved in a consensus conference with a senior research psychiatrist (G.L.B.). For this study, intermittent explosive disorder was diagnosed according to DSM-III37 criteria to replicate the methods of our previous studies.32 Antisocial personality (ASP) is defined herein as having a diagnosis of either ASP disorder or intermittent explosive disorder. Alcoholism was defined as DSM-III-R alcohol abuse (n=58) or alcohol dependence (n=252). The Karolinska Scales of Personality (KSP)38,39 were administered by a social worker to all subjects. The KSP were developed to measure dimensions of personalities and are derived from theories of biologically based temperament dimensions.3840 The KSP have 135 questions grouped into 15 scales that measure a subject's habitual behaviors and feelings. The scales are normalized for the Swedish population and measure relatively stable personality traits. The KSP is the most commonly used psychological test in genetic studies on offenders in Scandinavia. The socialization scale consists of questions from the California Psychological Inventory,41 which, in turn, was derived from the Delinquency Scale.42

All 804 subjects were studied for a history of suicide attempts by review of their medical records and responses to the Brown-Goodwin and family history questionnaires that were administered by a social worker. Suicidal gestures were suicidal acts in which the wrist was superficially cut so as to require only suturing. All other attempts were classified as severe. Severe suicide attempts included attempts by violent methods and large overdoses with tricyclic depressants or sedatives. Attempts characterized by low doses of sedatives resulting in somnolence only were excluded.

To use our current clinical data on the Finns, the data on the subjects used in our 1994 study were updated if in the interim a subject had a suicide attempt or if an offender committed a new index crime. One control who was previously free of any suicide attempts made 3 attempts. In addition, 7 impulsive offenders, 1 nonimpulsive offender, and 3 relatives who were previously free of suicide attempts attempted suicide. One nonimpulsive offender was reclassified as impulsive and 11 impulsive offenders were reclassified as nonimpulsive on the basis of the characteristics of the most recent violent crime committed after the release from prison.

GENOTYPE ANALYSIS

The TPH genotype was determined in 804 subjects by single-strand conformational polymorphism analysis.16,43 All genotype analyses were performed by individuals unaware of the diagnosis, biochemical, or clinical status of the subjects.

STATISTICAL AND LINKAGE ANALYSIS

Population associations were analyzed by χ2, analysis of variance, and Fisher exact tests (StatView, version 4.51; Abacus Concepts Inc, Berkeley, Calif). Significance was obtained when P≤.05. The SIBPAL module of the SAGE package44 was used to evaluate linkage in sib pairs by means of identity by descent (IBD) sib-pair and Haseman-Elston regression analyses.45,46 The IBD sib-pair method evaluates the inheritance of alleles inherited identical by descent in discordant sib pairs and in concordant unaffected and affected sib pairs. Evidence for linkage can be obtained from any of the 3 sib-pair groups.47,48 In the Haseman-Elston method, the squared trait difference between siblings is regressed on the estimated proportion of marker alleles shared identical by descent. Numerical values were assigned to the presence of the behavior (either suicidality or alcoholism) with 0 indicating the absence of the behavior and 1 indicating its presence. A negative slope is supportive of linkage. Since the accuracy of sib-pair linkage analysis depends on large sampling approximations, P values were empirically determined by computer simulations. Simulations were performed by holding the phenotype, family structures, and population allele frequencies constant. The TPH alleles were randomly assigned to the founders of the pedigrees on the basis of their population frequency. A random allele from each parent was subsequently transmitted to offspring and analyzed for linkage of the phenotype by means of the SAGE SIBPAL module. By replicating this procedure 12000 times, a simulated distribution was created that was used to obtain the simulation-derived P values.

QUANTIFICATION OF CSF 5-HIAA

Cerebrospinal fluid was obtained by lumbar puncture between 8 and 9 AM after overnight bed rest. The 5-HIAA in the first 12-mL aliquot of CSF was quantitated by high-performance liquid chromatography with electrochemical detection.49 The CSF 5-HIAA concentration was determined in 79 offenders and 33 controls.

DEMOGRAPHIC VARIABLES

The demographics of the replication and combined groups used in this study are listed separately in Table 1. The replication group was used to directly test our earlier finding of an association of TPH genotype to suicidal behavior32 and includes all unrelated subjects who were not in our previous study.

ASSOCIATION OF TPH GENOTYPE TO SUICIDALITY IN A NEW GROUP OF OFFENDERS

To replicate our previous finding32 of an association of TPH genotype to suicidal behavior, we performed a population association analysis (Table 2) on a new sample of Finnish offenders and controls who were not used in our previous study (Table 1).32 A significant association of TPH genotype to suicidality was observed in the impulsive offenders group (P=.001, Cramer V=0.34). Genotypes containing the 779C allele (L allele)33 were associated with a higher incidence of suicidality in the impulsive group (72% for the 779A/779C genotype, 59% for the 779C/779C genotype, and 31% for the 779A/779A genotype). However, in the nonimpulsive group, a significant association of TPH genotype to suicidality was observed in the opposite direction (P=.03, Cramer V=0.33). Genotypes with the 779C allele were associated with a lower incidence of suicidality (32% for the 779A/779C genotype, 56% for the 779A/779A genotype, and 80% for the 779C/779C genotype).

Table Graphic Jump LocationTable 2. Population Association Between Tryptophan Hydroxylase Genotype and History of Suicide Attempts in the Replication Group

We investigated whether there was a stronger association of TPH genotype to the more medically damaging, severe suicide attempts (Table 3). The association of TPH genotype to severe suicide attempts was highly significant (P<.001, Cramer V=0.39), indicating that the strength of the previous results in Table 2 derive primarily from the severe suicide attempts.

Table Graphic Jump LocationTable 3. Population Association Between Tryptophan Hydroxylase Genotype and History of Severe Suicide Attempts in the Replication Group

The TPH genotype was analyzed in relation to CSF 5-HIAA level in the new group of Finns (Table 4). However, we were unable to replicate the previously observed association of TPH genotype to CSF 5-HIAA level in the impulsive offenders. The only major difference between subjects with and without CSF 5-HIAA measurements (Table 5) was that subjects with CSF 5-HIAA measurements included a larger proportion of suicide attempters.

Table Graphic Jump LocationTable 4. Lack of Association Between Tryptophan Hydroxylase Genotype and 5-Hydroxyindoleacetic Acid (5-HIAA) Concentration in the Replication Group
Table Graphic Jump LocationTable 5. Demographics of Subjects Used in the CSF 5-HIAA Analysis and the Remainder of the Replication Group*
ASSOCIATION OF TPH GENOTYPE TO SUICIDALITY IN THE COMBINED GROUP

When the replication group was combined with the subjects used in our 1994 study,32 the association of TPH genotype and suicidality was strengthened (Table 6). In this combined analysis, a highly significant association (P<.001, Cramer V=0.34) was observed in the impulsive offender group. The nonimpulsive group did not have the increased frequency of suicides in subjects with 779A/779A genotypes that was observed in Table 2 with the replication group. In fact, in the combined sample a lower 779A allele frequency was found in the suicide attempters group in both the nonimpulsive (0.42 vs 0.48) and impulsive (0.41 vs 0.57) groups. When the offenders were combined, the association remained significant (P=.01, Cramer V=0.18). As mentioned above, the presence of the 779C allele was associated with an increase in the presence of suicide attempts in the impulsive group (75% for the 779A/779C genotype, 67% for the 779C/779C genotype, and 32% for the 779A/779A genotype) and in the total offender group (60% for the 779A/779C genotype, 64% for the 779C/779C genotype, and 39% for the 779A/779A).

Table Graphic Jump LocationTable 6. Population Association Between Tryptophan Hydroxylase Genotype and History of Suicide Attempts in the Combined Group

There was a significant difference in the TPH I7779A allele frequency between offenders who had not attempted suicide and controls (Table 6) in the combined group. The offenders with suicidality had essentially the same I7779A allele frequency as controls without suicidality (0.41 vs 0.43; Fisher exact P=.66). However, offenders who had not attempted suicide had a significantly higher I7779A allele frequency than controls (0.53 vs 0.43, Fisher exact P=.002) or suicide attempters (0.53 vs 0.41, Fisher exact P=.01).

An analysis of the association of TPH genotype to severe suicidal behavior was performed in the combined sample. As seen in Table 7, the association of TPH to suicidality was strengthened when only the severe suicide attempts were examined in the impulsive (P<.001, Cramer V=0.37), nonimpulsive (P=.03, Cramer V=0.29), and all (P=.007, Cramer V=0.20) offenders groups.

Table Graphic Jump LocationTable 7. Population Association Between Tryptophan Hydroxylase Genotype and History of Severe Suicide Attempts in the Combined Group
LINKAGE OF TPH GENOTYPE TO SUICIDALITY IN FINNISH FAMILIES

Analysis of linkage to suicidality was conducted by means of the IBD sib-pair and Haseman-Elston methods.46 Analyses were performed with 243 unaffected, 102 discordant, and 21 affected sib pairs. The demographics of the subjects used in the sib-pair analyses are presented in Table 8. These families included subjects from both the previous study32 and the replication sample. Linkage of suicidality to TPH is presented in Table 9. The IBD sib-pair analysis demonstrated significant evidence of linkage in the concordant unaffected sib pairs (simulation-derived P=.006). The deviations from expectation for the alleles IBD in the unaffected and discordant sib pairs are consistent with linkage. A trend toward evidence of linkage was observed by the Haseman-Elston method (Table 10).

Table Graphic Jump LocationTable 8. Demographics of Sib-Pair Analysis Subjects*
Table Graphic Jump LocationTable 9. IBD Sib-Pair Analysis of Suicidality/Severe Suicide Attempts and TPH I7 A779C Variant*
Table Graphic Jump LocationTable 10. Haseman-Elston Regression Analysis of Suicidality/Severe Suicide Attempts and TPH I7 A779C Variant*

When the sib pairs were analyzed for linkage to severe suicides (Table 9), the support for linkage in the IBD analysis again was derived from the unaffected sib pairs (simulation-derived P=.006). The deviations from expectation for the alleles IBD were also consistent with linkage. Haseman-Elston regression analysis reached significance (simulation-derived P=.01), providing further evidence of linkage (Table 10). Therefore, it apears that the strength of the linkage of TPH to suicidality was derived primarily from the severe suicide attempts.

LINKAGE OF TPH GENOTYPE TO ALCOHOLISM IN FINNISH FAMILIES

Linkage analysis of TPH genotype to alcoholism was performed with the 158 unaffected, 87 discordant, and 124 affected sib pairs available (Table 11) who were diagnosed by DSM-III-R criteria. The IBD sib-pair analysis demonstrated significant evidence of linkage in the unaffected sib pairs (simulation-derived P=.003). Consistent with linkage is the deviation from expectation of the alleles IBD. Significant linkage was also observed by Haseman-Elston regression analysis (simulation-derived P=.02) (Table 12).

Table Graphic Jump LocationTable 11. IBD Sib-Pair Analysis of Alcoholism/Non-ASP Alcoholism and TPH I7 A779C Variant*
Table Graphic Jump LocationTable 12. Haseman-Elston Regression Analysis of Alcoholism/Non-ASP Alcoholism and TPH I7 A779C Variant*

Because of the convergence of alcoholism with ASP traits with the type 2 alcoholism subtype, which has been shown to have a greater heritability than type 1 alcoholism,4,50 we investigated linkage of TPH to alcoholism with or without ASP. The unaffected and discordant sib pairs in the IBD sib-pair analysis provided evidence of linkage (Table 11, simulation-derived P<.001 and .006, respectively). Deviation from expectation of alleles IBD was also observed, consistent with linkage. Evidence of linkage by the Haseman-Elston method of TPH to alcoholism became stronger when alcoholics who did not have ASP were assessed (simulation-derived P<.001) (Table 12).

LINKAGE TO KSP IN FINNISH FAMILIES

To further investigate the hypothesis that the linkage of TPH to alcoholism may be caused by a potential relationship of TPH genotype to personality, linkage analysis using the Haseman-Elston sib-pair method was performed with the use of TPH genotype vs scores on the KSP (Table 13). The results of this post hoc linkage analysis are shown in Table 13. A significant linkage to socialization score was observed (simulation-derived P=.002; significant at 5% after controlling for multiple comparisons). No linkage of TPH to other KSP scores was detected.

Table Graphic Jump LocationTable 13. Sib-Pair Regression Analysis for KSP vs TPH I7 A779C Variant*

We replicated our previous finding32 of an association of TPH genotype with suicidality among impulsive Finnish offenders in a new group of offenders. When the replication sample and the previous sample of offenders were combined, the association became more robust. The strength of this association was derived from the severe suicide attempts within the impulsive group. It was in the impulsive group that the association between CSF 5-HIAA and TPH genotype was previously observed.32 However, we were unable to replicate this aspect of the association.

The observation in this replication study of an inverse association of TPH genotype to suicidality in the nonimpulsive group is consistent with the findings by Mann and colleagues.52 However, this inverse association was not detected in our combined group. In 1995 Abbar et al34 reported a study whose meaning is difficult to interpret.53 No association was found between an undefined TPH variant whose linkage disequilibrium to the TPH I7 A779C polymorphism is unknown and suicidality in French psychiatric patients of mixed ethnicity including few alcoholics. In the Abbar et al study, a nonsignificant trend toward association between TPH and suicidality was observed in the antisocial personality group, the group most resembling the impulsive offenders we have studied.

The strength of the TPH linkage to suicidality was derived from the severe suicide attempts. These attempts included those that met the violent suicide classification used by others.9,54,55 Previous studies have differentiated violent and nonviolent suicide groups on the basis of CSF 5-HIAA,9 platelet monoamine oxidase activity,54 urinary cortisol level, and norepinephrine-epinephrine ratio.55 Presumably, linkage of suicidality to TPH indicates that a gene in the vicinity of the TPH marker is influencing biochemical variables that affect suicidality.

The observed P values in our linkage analysis were verified with computer simulations to control for type I errors. This is important because we have observed (data not shown) that sib-pair linkage analysis can yield inflated P values when the trait is infrequent or sample size is small.

Suicidality was highest among offenders with either 1 or 2 I7779C alleles in the combined study, similar to our original findings.32 Individuals with either 1 or 2 I7779C alleles had an increased odds ratio (5.5 times for the impulsive group, 2.4 times for the all-offenders group; Table 6) of having attempted suicide or severe suicide (6.6 times for the impulsive group, 2.7 times for the all-offenders group; Table 7) indicating that the I7779C allele was associated with increased vulnerability to suicidality. The higher 779A allele frequency among offenders without suicide attempts could be caused by this allele having a protective effect within a group at high risk for suicide.

Surprisingly, the strength of the linkage of TPH to alcoholism was derived from alcoholics without ASP. Cloninger et al4 defined 2 classes of alcoholics: type 1 and type 2. Type 1 alcoholics are characterized by a late age at onset and anxious personality traits. Type 2 alcoholics are male, have an early age at onset, and exhibit antisocial traits. However, the alcoholics without ASP comorbidity in the present sample had other personality disorders, particularly borderline personality disorder, confounding the classification of these alcoholics as type 1 or 2. Because of the recruitment of this sample through alcoholic offenders, this sample may be atypical in having a serotonin-associated risk factor, or this may be a typical feature of type 1 alcoholics. Such a result could be consistent with a recent report that a functional serotonin transporter polymorphism, 5HTTLPR, was associated with anxiety-related traits.18

Finally, a linkage of TPH genotype to KSP socialization score was observed. Low socialization scores are the result of general dissatisfaction, poor family and school adjustment, and negative childhood experiences. The genetic influences that lead to suicidality and alcoholism may also affect KSP socialization scores. Nordström et al56 have shown that suicide attempters have significantly lower KSP socialization scale scores than controls. Since TPH was linked and associated with suicidality, linkage of TPH to KSP socialization score was not unexpected.

Previous studies have identified several genes associated with alcoholism. Asian alcoholics have significantly lower frequencies of a variant aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH2, ADH3) alleles.5759 Although several reports demonstrated an association between the D2 dopamine receptor and alcoholism,60,61 a meta-analysis demonstrated no significant association.62

This Finnish cohort has proved useful for the study of behavioral traits. Advantages of this group are that Finns are a population isolate more genetically homogeneous than most other Western populations. Their suicide rate is the third highest among industrialized nations,63 and their alcoholism rate is relatively low.64 The offenders are a violent, behaviorally extreme sample consisting primarily of murderers, violent sexual offenders, and fire setters. More than half have attempted suicide, and all but 3 of the psychiatrically interviewed offenders were alcoholic.

If the linkage and association results reflect an effect of TPH on behavior, it is highly likely that the effect is not caused by the TPH I7 A779C polymorphism itself but, rather, by another functional variant within the TPH gene or a nearby gene. Association of a trait with a marker generally indicates that the functional variant(s) is nearby, whereas linkage can occur over much greater distances. Tryptophan hydroxylase is located on the short arm of chromosome 11 at p15.4-15.5.16 Tyrosine hydroxylase and D4 dopamine receptor genes are located nearby and are involved in neurotransmitter metabolism. However, the tyrosine hydroxylase gene has been shown to exert no influence on alcoholism,65 and no association was found between D4 dopamine receptor and alcoholism6567 or monoamine metabolite concentrations.66

The linkage and association results presented herein indicate that the TPH intron 7 polymorphism, or another mutation(s) nearby, is involved in suicidality, alcoholism, and socialization. No other specific genetic components of suicidality have been identified, although the recent report of familial transmission of suicidal behavior2 is consistent with our findings. Since suicidality and alcoholism are likely to be complex, multifactorial phenotypes, TPH may turn out to be one of several genes involved.

Accepted for publication March 24, 1998.

Some of the results were obtained by means of the SAGE software package, which is supported by Public Health Service Resource Grant 1 P41 RR03655 from the Division of Research Resources.

We thank Julie Humphreys, Bita Nakhai, PhD, and Kimberly Jefferson for assistance in single strand conformation polymorphism analysis; Longina Akhtar, MS, for preparation and maintenance of the lymphoblast cell lines; Kaija Sutinen, MS, for the collection of data on the Finnish cohort; Marie Walters, Michael Eckardt, PhD, and Betsy Davis for assistance with the Finnish database; and Susan Goodson, MD, Wendol Williams, MD, and Paul Ragan, MD, for blind rating the diagnoses.

Reprints: David A. Nielsen, PhD, National Institute on Alcohol Abuse and Alcoholism, Section of Molecular Genetics, Park V, Room 451, 12420 Parklawn Dr, Rockville, MD 20852 (e-mail: nielsen@helix.nih.gov).

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Erdmann  JShimron-Abarbanell  DCichon  SAlbus  MMaier  WLichtermann  DMinges  JReuner  UFranzek  EErtl  MAHebebrand  JRemschmidt  HLehmkuhl  GPoustka  FSchmidt  MFimmers  RKörner  JRietschel  MPropping  PNöthen  M Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene. Am J Med Genet. 1995;60393- 399
Ozaki  NLappalainen  JDean  MVirkkunen  MLinnoila  MGoldman  D Mapping of the serotonin 5-HT1D alpha autoreceptor gene (HTR1D) on chromosome 1 using a silent polymorphism in the coding region. Am J Med Genet. 1995;60162- 164
Lappalainen  JDean  MCharbonneau  LVirkkunen  MLinnoila  MGoldman  D Mapping of the serotonin 5-HT1D beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants. Am J Med Genet. 1995;60157- 161
Nothen  MMErdmann  JShimron-Abarbanell  DPropping  P Identification of genetic variation in the human serotonin 1D beta receptor gene. Biochem Biophys Res Commun. 1994;2051194- 1200
Shimron-Abarbanell  DHarms  HErdmann  JAlbus  MMaier  WRietschel  MKorner  JWeigelt  BFranzek  ESander  TKnapp  MPropping  PNothen  MM Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia. Am J Med Genet. 1996;67225- 228
Ozaki  NManji  HLubierman  VLu  SJLappalainen  JRosenthal  NEGoldman  D A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization. Biol Psychiatry. 1996;401267- 1272
Erdmann  JShimron-Abarbanell  DRietschel  MAlbus  MMaier  WKorner  JBondy  BChen  KShih  JCKnapp  MPropping  PNothen  MM Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet. 1996;97614- 619
Lappalainen  JZhang  LDean  MOz  MOzaki  NYu  DHVirkkunen  MWeight  FLinnoila  MGoldman  D Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Genomics. 1995;27274- 279
Gelernter  JRao  PAPauls  DLHamblin  MWSibley  DRKidd  KK Assignment of the 5HT7 receptor gene (HTR7) to chromosome 10q and exclusion of genetic linkage with Tourette syndrome. Genomics. 1995;26207- 209
Cooper  JRMelcer  I The enzymatic oxidation of tryptophan to 5-hydroxytryptophan in the biosynthesis of serotonin. J Pharmacol Exp Ther. 1961;132265- 268
Nielsen  DAGoldman  DVirkkunen  MTokola  RRawlings  RLinnoila  M Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen Psychiatry. 1994;5134- 38
Nielsen  DAJenkins  GLStefanisko  KMJefferson  KKGoldman  D Sequence, splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7. Mol Brain Res. 1997;45145- 148
Abbar  MCourtet  PAmadeo  SCaer  YMallet  JBaldy-Moulinier  MCastelnau  DMalafosse  A Suicidal behaviors and the tryptophan hydroxylase gene. Arch Gen Psychiatry. 1995;52846- 849
Virkkunen  MEggert  MRawlings  RLinnoila  M A prospective follow-up study of alcoholic violent offenders and fire setters. Arch Gen Psychiatry. 1996;53523- 529
American Psychiatric Association, Committee on Nomenclature and Statistics, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
American Psychiatric Association, Committee on Nomenclature and Statistics, Diagnostic and Statistical Manual of Mental Disorders, Third Edition.  Washington, DC American Psychiatric Association1987;
Schalling  DAsberg  M Biological and psychological correlation of impulsiveness and monotony avoidance. Strelau  JFarlay  FMGale  AedsThe Biological Foundations of Personality and Behavior. New York, NY Hemisphere Press1981;181- 194
Schalling  D Psychopathy related personality variables and the psychophysiology of socialization. Hare  RDSchalling  DedsPsychopathic Behaviour Approaches to Research. Chicester, England Wiley1987;85- 106
Schalling  DAsberg  MEdman  GOreland  L Markers for vulnerability to psychopathology: temperament traits associated with platelet MAO activity. Acta Psychiatr Scand. 1987;76172- 182
Rosen  A-SSchalling  D On the validity of the CPI socialization scale. J Consult Clin Psychol. 1974;42757- 765
Gough  HG Theory and measurement of socialization. J Consult Clin Psychol. 1960;7423- 30
Nielsen  DANovoradovsky  AGoldman  D SSCP primer design based on single-strand DNA structure predicted by a DNA folding program. Nucleic Acids Res. 1995;232287- 2291
Not Available, SAGE: Statistical Analysis for Genetic Epidemiology, Release 2.2.  New Orleans, La Department of Biometry and Genetics, LSU Medical Center1994;
Elston  RC 1996 William Allan Award Address: algorithms and inferences: the challenge of multifactorial diseases. Am J Hum Genet. 1997;60255- 262
Haseman  JKElston  RC The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972;23- 19
Zhang  HRisch  N Mapping quantitative-trait loci in humans by use of extreme concordant sib pairs: selected sampling by parental phenotypes. Am J Hum Genet. 1996;59951- 957
Risch  NJZhang  H Mapping quantitative trait loci with extreme discordant sib pairs: sampling considerations. Am J Hum Genet. 1996;58836- 843
Scheinin  MChang  WHKirk  KLLinnoila  M Simultaneous determination of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high-performance liquid chromatography using electrochemical detection. Anal Biochem. 1983;131246- 253
Sigvardsson  SBohman  MCloninger  CR Replication of the Stockholm Adoption Study of alcoholism: confirmatory cross-fostering analysis. Arch Gen Psychiatry. 1996;53681- 687
Fry  JC Biological data analysis: a practical approach. Fry  JCedPractical Approach Series. Oxford, England Oxford University Press1996;102
Mann  JJMalone  KMNielsen  DAGoldman  DErdos  JGelernter  J Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry. 1997;1541451- 1453
Nielsen  DAGoldman  DVirkkunen  MTokola  RRawlings  RLinnoila  M TPH replication study: not! Arch Gen Psychiatry. 1996;53964- 965
Gottfries  CGvon Knorring  LOreland  L Platelet monoamine oxidase activity in mental disorders, 2: affective psychoses and suicidal behavior. Prog Neuropsychopharmacol. 1980;4185- 192
Prasad  AJ Neuroendocrine differences between violent and non-violent parasuicides. Neuropsychobiology. 1985;13157- 159
Nordstrom  PGustavsson  PEdman  GAsberg  M Temperamental vulnerability and suicide risk after attempted suicide. Suicide Life Threat Behav. 1996;26380- 394
Thomasson  HRCrabb  DWEdenberg  HJLi  TKHwu  HGChen  CCYeh  EKYin  SJ Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders. Alcohol Clin Exp Res. 1994;18640- 643
Thomasson  HREdenberg  HJCrabb  DWMai  XLJerome  RELi  TKWang  SPLin  YTLu  RBYin  SJ Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet. 1991;48677- 681
Nakamura  KIwahashi  KMatsuo  YMiyatake  RIchikawa  YSuwaki  H Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase 2*2, I: a comparison of the genotypes of ALDH2, ADH2, ADH3, and cytochrome P-4502E1 between alcoholics and nonalcoholics. Alcohol Clin Exp Res. 1996;2052- 55
Blum  KNoble  EPSheridan  PJMontgomery  ARitchie  TJagadeeswaran  PNogami  HBriggs  AHCohn  JB Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA. 1990;2632055- 2060
Lawford  BRYoung  RMRowell  JAGibson  JNFeeney  GFXRitchie  TLSyndulko  KNoble  EP Association of the D2 dopamine receptor A1 allele with alcoholism: medical severity of alcoholism and type of controls. Biol Psychiatry. 1997;41386- 393
Gelernter  JGoldman  DRisch  N The A1 allele at the D2 dopamine receptor gene and alcoholism: a reappraisal. JAMA. 1993;2691673- 1677
Lester  D The availability of firearms and the use of firearms for suicide: a study of 20 countries. Acta Psychiatr Scand. 1990;81146- 147
Eronen  MHakola  PTiihonen  J Mental disorders and homicidal behavior in Finland. Arch Gen Psychiatry. 1996;53497- 501
Geijer  TJonsson  ENeiman  JPersson  M-LBrene  SGyllander  ASedvall  GRydberg  UWasserman  DTerenius  L Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics. Alcohol Clin Exp Res. 1997;2139- 39
Adamson  MDKennedy  JPetronis  ADean  MVirkkunen  MLinnoila  MGoldman  D DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls. Am J Med Genet. 1995;60199- 205
Chang  F-MKo  H-CLu  R-BPakstis  AJKidd  KK The dopamine D4 receptor gene (DRD4) is not associated with alcoholism in three Taiwanese populations: six polymorphisms tested separately and as haplotypes. Biol Psychiatry. 1997;41393- 405

Figures

Tables

Table Graphic Jump LocationTable 1. Demographics of the Finnish Subjects*
Table Graphic Jump LocationTable 2. Population Association Between Tryptophan Hydroxylase Genotype and History of Suicide Attempts in the Replication Group
Table Graphic Jump LocationTable 3. Population Association Between Tryptophan Hydroxylase Genotype and History of Severe Suicide Attempts in the Replication Group
Table Graphic Jump LocationTable 4. Lack of Association Between Tryptophan Hydroxylase Genotype and 5-Hydroxyindoleacetic Acid (5-HIAA) Concentration in the Replication Group
Table Graphic Jump LocationTable 5. Demographics of Subjects Used in the CSF 5-HIAA Analysis and the Remainder of the Replication Group*
Table Graphic Jump LocationTable 6. Population Association Between Tryptophan Hydroxylase Genotype and History of Suicide Attempts in the Combined Group
Table Graphic Jump LocationTable 7. Population Association Between Tryptophan Hydroxylase Genotype and History of Severe Suicide Attempts in the Combined Group
Table Graphic Jump LocationTable 8. Demographics of Sib-Pair Analysis Subjects*
Table Graphic Jump LocationTable 9. IBD Sib-Pair Analysis of Suicidality/Severe Suicide Attempts and TPH I7 A779C Variant*
Table Graphic Jump LocationTable 10. Haseman-Elston Regression Analysis of Suicidality/Severe Suicide Attempts and TPH I7 A779C Variant*
Table Graphic Jump LocationTable 11. IBD Sib-Pair Analysis of Alcoholism/Non-ASP Alcoholism and TPH I7 A779C Variant*
Table Graphic Jump LocationTable 12. Haseman-Elston Regression Analysis of Alcoholism/Non-ASP Alcoholism and TPH I7 A779C Variant*
Table Graphic Jump LocationTable 13. Sib-Pair Regression Analysis for KSP vs TPH I7 A779C Variant*

References

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Cloninger  CRBohman  MSigvardsson  S Inheritance of alcohol abuse: cross-fostering analysis of adopted men. Arch Gen Psychiatry. 1981;38861- 868
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Rosenthal  NEDavenport  YCowdry  RWWebster  MHGoodwin  FK Monoamine metabolites in cerebrospinal fluid of depressive subgroups. Psychiatry Res. 1980;2113- 119
Asberg  MTraskman  LThoren  P 5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor? Arch Gen Psychiatry. 1976;331193- 1197
Virkkunen  MDe Jong  JBartko  JLinnoila  M Psychobiological concomitants of history of suicide attempts among violent offenders and impulsive fire setters. Arch Gen Psychiatry. 1989;46604- 606
Roy  ADe Jong  JLinnoila  M Cerebrospinal fluid monoamine metabolites and suicidal behavior in depressed patients. Arch Gen Psychiatry. 1989;46609- 612
Ballenger  JCGoodwin  FKMajor  LFBrown  GL Alcohol and central serotonin metabolism in man. Arch Gen Psychiatry. 1979;36224- 227
Fils-Aime  MLEckardt  MJGeorge  DTBrown  GLMefford  ILinnoila  M Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics. Arch Gen Psychiatry. 1996;53211- 216
Higley  JDThompson  WWChampoux  MGoldman  DHasert  MFKraemer  GWScanlan  JMSuomi  SJLinnoila  M Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoamine metabolites in rhesus monkeys (Macaca mulatta). Arch Gen Psychiatry. 1993;50615- 623
Brunner  HGNelen  MBreakefield  XORopers  HHvan Oost  BA Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science. 1993;262578- 580
Nielsen  DADean  MGoldman  D Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Am J Hum Genet. 1992;511366- 1371
Ichinose  HOhye  TTakahashi  ESeki  NHori  TSegawa  MNomura  YEndo  KTanaka  HTsuji  SFujita  KNagatsu  T Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994;8236- 242
Lesch  KPBengel  DHeils  ASabol  SZGreenberg  BDPetri  SBenjamin  JMuller  CRHamer  DHMurphy  DL Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;2741527- 1531
Ogilvie  ADBattersby  SBubb  VJFink  GHarmar  AJGoodwin  GMSmith  CA Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet. 1996;347731- 733
Nakhai  BNielsen  DALinnoila  MGoldman  D Two naturally occurring amino acid substitutions in the human 5-HT1A receptor: glycine 22 to serine 22 and isoleucine 28 to valine 28. Biochem Biophys Res Commun. 1995;210530- 536
Rotondo  ANielsen  DANakhai  BHulihan-Giblin  BBolos  AGoldman  D Agonist-promoted down-regulation and functional desensitization in two naturally-occurring variants of the human serotonin1A receptor. Neuropsychopharmacology. 1997;1718- 26
Erdmann  JShimron-Abarbanell  DCichon  SAlbus  MMaier  WLichtermann  DMinges  JReuner  UFranzek  EErtl  MAHebebrand  JRemschmidt  HLehmkuhl  GPoustka  FSchmidt  MFimmers  RKörner  JRietschel  MPropping  PNöthen  M Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene. Am J Med Genet. 1995;60393- 399
Ozaki  NLappalainen  JDean  MVirkkunen  MLinnoila  MGoldman  D Mapping of the serotonin 5-HT1D alpha autoreceptor gene (HTR1D) on chromosome 1 using a silent polymorphism in the coding region. Am J Med Genet. 1995;60162- 164
Lappalainen  JDean  MCharbonneau  LVirkkunen  MLinnoila  MGoldman  D Mapping of the serotonin 5-HT1D beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants. Am J Med Genet. 1995;60157- 161
Nothen  MMErdmann  JShimron-Abarbanell  DPropping  P Identification of genetic variation in the human serotonin 1D beta receptor gene. Biochem Biophys Res Commun. 1994;2051194- 1200
Shimron-Abarbanell  DHarms  HErdmann  JAlbus  MMaier  WRietschel  MKorner  JWeigelt  BFranzek  ESander  TKnapp  MPropping  PNothen  MM Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia. Am J Med Genet. 1996;67225- 228
Ozaki  NManji  HLubierman  VLu  SJLappalainen  JRosenthal  NEGoldman  D A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization. Biol Psychiatry. 1996;401267- 1272
Erdmann  JShimron-Abarbanell  DRietschel  MAlbus  MMaier  WKorner  JBondy  BChen  KShih  JCKnapp  MPropping  PNothen  MM Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet. 1996;97614- 619
Lappalainen  JZhang  LDean  MOz  MOzaki  NYu  DHVirkkunen  MWeight  FLinnoila  MGoldman  D Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Genomics. 1995;27274- 279
Gelernter  JRao  PAPauls  DLHamblin  MWSibley  DRKidd  KK Assignment of the 5HT7 receptor gene (HTR7) to chromosome 10q and exclusion of genetic linkage with Tourette syndrome. Genomics. 1995;26207- 209
Cooper  JRMelcer  I The enzymatic oxidation of tryptophan to 5-hydroxytryptophan in the biosynthesis of serotonin. J Pharmacol Exp Ther. 1961;132265- 268
Nielsen  DAGoldman  DVirkkunen  MTokola  RRawlings  RLinnoila  M Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen Psychiatry. 1994;5134- 38
Nielsen  DAJenkins  GLStefanisko  KMJefferson  KKGoldman  D Sequence, splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7. Mol Brain Res. 1997;45145- 148
Abbar  MCourtet  PAmadeo  SCaer  YMallet  JBaldy-Moulinier  MCastelnau  DMalafosse  A Suicidal behaviors and the tryptophan hydroxylase gene. Arch Gen Psychiatry. 1995;52846- 849
Virkkunen  MEggert  MRawlings  RLinnoila  M A prospective follow-up study of alcoholic violent offenders and fire setters. Arch Gen Psychiatry. 1996;53523- 529
American Psychiatric Association, Committee on Nomenclature and Statistics, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
American Psychiatric Association, Committee on Nomenclature and Statistics, Diagnostic and Statistical Manual of Mental Disorders, Third Edition.  Washington, DC American Psychiatric Association1987;
Schalling  DAsberg  M Biological and psychological correlation of impulsiveness and monotony avoidance. Strelau  JFarlay  FMGale  AedsThe Biological Foundations of Personality and Behavior. New York, NY Hemisphere Press1981;181- 194
Schalling  D Psychopathy related personality variables and the psychophysiology of socialization. Hare  RDSchalling  DedsPsychopathic Behaviour Approaches to Research. Chicester, England Wiley1987;85- 106
Schalling  DAsberg  MEdman  GOreland  L Markers for vulnerability to psychopathology: temperament traits associated with platelet MAO activity. Acta Psychiatr Scand. 1987;76172- 182
Rosen  A-SSchalling  D On the validity of the CPI socialization scale. J Consult Clin Psychol. 1974;42757- 765
Gough  HG Theory and measurement of socialization. J Consult Clin Psychol. 1960;7423- 30
Nielsen  DANovoradovsky  AGoldman  D SSCP primer design based on single-strand DNA structure predicted by a DNA folding program. Nucleic Acids Res. 1995;232287- 2291
Not Available, SAGE: Statistical Analysis for Genetic Epidemiology, Release 2.2.  New Orleans, La Department of Biometry and Genetics, LSU Medical Center1994;
Elston  RC 1996 William Allan Award Address: algorithms and inferences: the challenge of multifactorial diseases. Am J Hum Genet. 1997;60255- 262
Haseman  JKElston  RC The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972;23- 19
Zhang  HRisch  N Mapping quantitative-trait loci in humans by use of extreme concordant sib pairs: selected sampling by parental phenotypes. Am J Hum Genet. 1996;59951- 957
Risch  NJZhang  H Mapping quantitative trait loci with extreme discordant sib pairs: sampling considerations. Am J Hum Genet. 1996;58836- 843
Scheinin  MChang  WHKirk  KLLinnoila  M Simultaneous determination of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high-performance liquid chromatography using electrochemical detection. Anal Biochem. 1983;131246- 253
Sigvardsson  SBohman  MCloninger  CR Replication of the Stockholm Adoption Study of alcoholism: confirmatory cross-fostering analysis. Arch Gen Psychiatry. 1996;53681- 687
Fry  JC Biological data analysis: a practical approach. Fry  JCedPractical Approach Series. Oxford, England Oxford University Press1996;102
Mann  JJMalone  KMNielsen  DAGoldman  DErdos  JGelernter  J Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry. 1997;1541451- 1453
Nielsen  DAGoldman  DVirkkunen  MTokola  RRawlings  RLinnoila  M TPH replication study: not! Arch Gen Psychiatry. 1996;53964- 965
Gottfries  CGvon Knorring  LOreland  L Platelet monoamine oxidase activity in mental disorders, 2: affective psychoses and suicidal behavior. Prog Neuropsychopharmacol. 1980;4185- 192
Prasad  AJ Neuroendocrine differences between violent and non-violent parasuicides. Neuropsychobiology. 1985;13157- 159
Nordstrom  PGustavsson  PEdman  GAsberg  M Temperamental vulnerability and suicide risk after attempted suicide. Suicide Life Threat Behav. 1996;26380- 394
Thomasson  HRCrabb  DWEdenberg  HJLi  TKHwu  HGChen  CCYeh  EKYin  SJ Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders. Alcohol Clin Exp Res. 1994;18640- 643
Thomasson  HREdenberg  HJCrabb  DWMai  XLJerome  RELi  TKWang  SPLin  YTLu  RBYin  SJ Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet. 1991;48677- 681
Nakamura  KIwahashi  KMatsuo  YMiyatake  RIchikawa  YSuwaki  H Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase 2*2, I: a comparison of the genotypes of ALDH2, ADH2, ADH3, and cytochrome P-4502E1 between alcoholics and nonalcoholics. Alcohol Clin Exp Res. 1996;2052- 55
Blum  KNoble  EPSheridan  PJMontgomery  ARitchie  TJagadeeswaran  PNogami  HBriggs  AHCohn  JB Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA. 1990;2632055- 2060
Lawford  BRYoung  RMRowell  JAGibson  JNFeeney  GFXRitchie  TLSyndulko  KNoble  EP Association of the D2 dopamine receptor A1 allele with alcoholism: medical severity of alcoholism and type of controls. Biol Psychiatry. 1997;41386- 393
Gelernter  JGoldman  DRisch  N The A1 allele at the D2 dopamine receptor gene and alcoholism: a reappraisal. JAMA. 1993;2691673- 1677
Lester  D The availability of firearms and the use of firearms for suicide: a study of 20 countries. Acta Psychiatr Scand. 1990;81146- 147
Eronen  MHakola  PTiihonen  J Mental disorders and homicidal behavior in Finland. Arch Gen Psychiatry. 1996;53497- 501
Geijer  TJonsson  ENeiman  JPersson  M-LBrene  SGyllander  ASedvall  GRydberg  UWasserman  DTerenius  L Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics. Alcohol Clin Exp Res. 1997;2139- 39
Adamson  MDKennedy  JPetronis  ADean  MVirkkunen  MLinnoila  MGoldman  D DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls. Am J Med Genet. 1995;60199- 205
Chang  F-MKo  H-CLu  R-BPakstis  AJKidd  KK The dopamine D4 receptor gene (DRD4) is not associated with alcoholism in three Taiwanese populations: six polymorphisms tested separately and as haplotypes. Biol Psychiatry. 1997;41393- 405

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