Table 2.

Published studies examining the contribution of candidate genes to psychiatric comorbidity

Disorders	Citation	Genetic Factors Examined	Sample	Measurement of disorders	Conclusions
Alcohol abuse (ALC) and CD	Samochowiec, J. et al. 1999. Psychiatry Research 86: 67–72	Candidate gene: functional 30-bp repeat polymorphism in the promoter region of the X-chromosomal monoamine oxidase A gene (MAOA)	488 male subjects of German descent (185 psychiatrically screened control subjects and 303 alcohol-dependent subjects)	Composite International Diagnostic Interview	The frequency of the low-activity 3-repeat allele was significantly higher in antisocial alcoholics compared to control subjects and to alcoholics without ASPD.
ALC and CD	Parsian, A. 1999. Genomics 55: 290–295.	Candidate genes: point mutation at position 941 in exon 8 and position 1460 of exon 14 of the MAO-A gene	Alcoholic group of 134 probands classified as alcoholics and 89 unrelated controls who met no DSM-III-R criteria for psychiatric disorders. All subjects are white Caucasians.	Alcoholism identified according to Feighner criteria for alcoholism, and alcoholism subtypes identified according to the criteria of Cloninger. DSM-III-R criteria	The mutant allele frequency of exon 8 and exon 14 was significantly different in type 2 alcoholics compared to normal controls. The MAO-A activity in alcoholics was lower than that in normal controls. The frequency of the nonmutated alleles, which are associated with low activity, are higher in alcoholic groups than normal controls.
ALC and CD	Parsian, A and Cloninger, CR. 2001. Psychiatric Genetics 11: 89–94.	Candidate genes: polymorphisms in tryptophan hydroxylase (TPH), serotonin receptors (5- HT2A and 5-HT2c), serotonin transporter (5-HTT) and monoamine oxidase A (MAO-A) genes	133 alcoholics. The normal control group consisted of 88 individuals who met no DSM-III-R criteria for affective disorders, alcoholism, or psychotic or drug-use disorders. All subjects were white Caucasians.	Alcoholism identified according to Feighner criteria and alcoholism subtypes identified according to Cloninger criteria. DSM-III-R criteria used to evaluate presence of psychiatric disorders.	The allele frequencies of the functional polymorphism in 5-HTTLPR were different in total alcoholics and type 2 alcoholics vs controls (higher frequencies of the long allele in alcoholics). Genotype frequencies were also different between type 2 alcoholics and controls: the former had an excess of LL homozygotes. No results were significant after correction for multiple testing.
ALC and CD	Saito, T et al. 2002. Psychiatry Research 109: 113– 119	Candidate genes: functional 30-bp repeat polymorphism in the promoter region of the MAOA gene	324 male subjects of Caucasian Finnish origin, including 172 alcoholics (114 type 1 and 58 type 2) and 152 control subjects.	Clinical interview with a physician, Michigan Alcoholism Screening Test, and Johns Hopkins Symptoms Checklist 90	No difference was found in allele distribution between type 1 and type 2 alcoholics. There was also no difference in the allele distribution when each group of alcoholics was compared with controls.
ALC and CD	Lu, RB et al.2003. Alcoholism: Clinical and Experimenta l Research 27(6): 889– 893.	Candidate genes: number of tandem repeats located upstream (uVNTR) and EcoRV at exon 14 of MAO-A	129 Han Chinese males: 41 with antisocial personality disorder (ASPD) and alcoholism, 50 with ASPD without alcoholism and 38 with a history of antisocial behavior. Also 77 community controls.	Modified Chinese Version of the Schedule of Affective Disorder and Schizophrenia-Lifetime. Used DSM-IV criteria.	Neither antisocial personality disorder nor antisocial alcoholism were associated with the alleles of the uVNTR and the EcoRV polymorphisms of the MAO-A gene tested individually either at each site or as a haplotype.
ALC and CD	Koller, G. et al. 2003. Alcohol and Alcoholism 38(1): 31– 34.	MAOAuVNTR functional polymorphism in the promoter region of the X-chromosomal monoamine oxidase (MAOA) gene	169 male alcoholic subjects and 72 controls of German descent	Brown-Goodwin Assessment for History of Lifetime Aggression, Buss Durkee Hostility Inventory, Barrat Impulsiveness Score	No significant differences were detected between the frequency of the three-repeat allele in the MAOA polymorphism and high or low scores of aggression, irritability, assault or impulsiveness in alcoholics, in comparison to controls.
ALC and CD	Hoenicka, J. et al Neurotoxicity Research 2007 11(1): 51–59	SNPs/microsatellites from four candidate genes: dopamine receptor gene (DRD2), dopamine transporter (SLC6A3), fatty acid amide hydrolase (FAAH) and the cannabinoid receptor type 1 (CNR1)	137 Spanish alcohol dependent adult males; those with childhood ADHD were excluded. 98 community controls free of psychiatric disorders.	International Personality Disorder Examination, Hare's Psychopathology Checklist Revised (PCL- R); DSM-IV ADU diagnosis verified using structured clinical interview, the Addiction Severity Index (ASI), and the Severity of Alcohol Dependence Scale (SADS)	There is a relation between the TaqIA SNP (DRD2 gene), FAAH and CNR1 genes and the PCL-R's Factor 1 (representing emotional detachment) in alcoholic patients. The relationship seems to be additive and independent and might be responsible for 11.4% of the variance in the PCL-R subscale.
ALC and CD	Wang, TJ et al. 2007. Progress in Neuro- Psychophar macology & Biological Psychiatry 31: 108–114	Candidate genes: number of tandem repeats located upstream (uVNTR) of the monoamine oxidase A (MAOA-u VNTR) and dopamine D2 receptor (DRD2) Taq1A polymorphism	231 Han Chinese males in Taiwan: 73 antisocial alcoholics and 158 antisocial non- alcoholics.	Chinese version of the Modified Schedule of Affective Disorder and Schizophrenia-Life Time (SADS-L)	Neither the DRD2 Taql A polymorphism nor the MAOA gene was associated with antisocial alcoholism (rather than non-alcoholic ASPD). However, among those with the MAOA-uVNTR 4-repeat polymorphism, the DRD2 A1/A2 genotype had a protective effect against alcoholism in ASPD subjects
ALC and CD	Dick, D. et al. 2008; Archives of General Psychiatry 65(3): 310– 318.	Linkage analyses using data from a genome-wide 10-cM microsatellite scan. Association analyses were conducted on 27 SNPs genotyped across the muscarinic acetylcholine receptor M2 gene (CURM2)	Approximately 2300 individuals from 262 families	Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview. Lifetime alcohol dependence was assessed using DSM-IV criteria; other lifetime diagnoses assessed using DSM-IIIR criteria.	Linkage analyses identified a region on chromosome 7 consistent with a gene that broadly predisposes individuals to externalizing behavior. Association analyses of CHRM2 suggest that it is involved in a general externalizing phenotype.
ALC and CD	Lee, SY et al. 2009. Alcoholism-- Clinical and Experinmenta l Research 33(6): 985– 990.	Candidate genes: genotypes of ALDH2 functional polymorphisms and MAOA-uVNTR	294 Han Chinese antisocial men in Taiwan including 132 ASPD with alcoholism and 162 without alcoholism	Modified Chinese Version of the Schedule of Affective Disorder and Schizophrenia-Lifetime. Used DSM-IV criteria.	A significant difference of ALDH2 polymorphisms was found among the 2 study groups. There was a significant interaction of MAOA and ALDH2 gene in antisocial ALC (odds ratio = 2.927; p = 0.032). The protective effects of the ALDH2*2 allele against alcoholism might disappear in subjects with ASPD and carrying MAOA-uVNTR 4-repeat allele in the Han Chinese male population.
ALC and impulsivenes s	Limosin F et al. 2005. European Psychiatry 20: 304–306.	Candidate gene frequency: Bal1 polymorphism in dopamine receptor D3 (DRD3)	108 French alcohol- dependent patients and 79 healthy controls	Interviews used the Diagnostic Interview for Genetic Studies (DIGS) and the Barratt Impulsiveness Scale (BIS-10).	Patients above the median value for cognitive impulsiveness were more frequently heterozygous for the gene coding for the DRD3 than alcohol-dependent patients without impulsiveness and healthy controls
ALC and neuro- psychological disorder	Rodriguez- Jimenez R. 2006. European Psychiatry 21:66–69.	Candidate gene: Taq1A polymorphism on Dopamine receptor D2 (DRD2)	50 Spanish male alcoholic patients w/o other substance consumption in past- year and 98 community controls free of disorders	Structured Clinical Interview for DSM-IV (SCID), Cattell Intelligence Scales (IQ), Continuous Performance test (AX version), and the Stop task.	Alcoholics carrying the Taq1 A1 allele present lower sustained attention and less inhibitory control than patients without such allele.
ALC and ADHD	Kim et al. Alcohol & Alcoholism 2006 41(4): 407–411	Candidate genes: DRD2, ALDH2, a regulatory region of the serotonin transporter (5- HTTLPR), and catechol-O- methyltransferase gene polymorphism (COMT)	85 Korean men who were diagnosed as having DSM-IV alcohol dependence (AD). Cases = comorbid ADHD and AD / Controls = AD diagnosis only	Barratt impulsiveness scale, Brief anger- aggression questionnaire, Overt aggression scale, Codependence test, Obsessive compulsive drinking scale	No significant differences in gene frequencies of DRD2, ALDH2, 5-HTTLPR or COMT polymorphisms between alcoholics with and without ADHD.
SA and CD	Stallings, MC 2005 Arch Gen Psych 62:1042– 1051	Quantitative train loci (QTL) that influence externalizing problem behavior - do they influence DV?	Cases: 249 adolescent sibling-pairs from 191 families. Controls: a community based sample of 4493 adolescents from Colorado	Composite International Diagnostic Interview - Substance Abuse Module (CIDI-SAM), Diagnostic Interview Schedule	For both DV and CDS, there was evidence of linkage to the same region on chromosome 9q34. Composite index (DV + CDS) yielded strongest evidence for linkage at this location.
SA and CD	Gerra, G. et al. 2005. Addiction Biology 10: 275–281	Candidate gene frequency: 3' untranslated region of exon 15 of the SLC6A3 gene coding for dopamine transporter (DAT)	125 Italian male subjects and 104 Italian male heroin-dependent subjects (including 52 with violent behavior and criminal records).	Structured Clinical Interviews for Axis I disorders (SCID) Italian version; Buss-Durkee Hostility Inventory (BDHI); antisocial behavior evaluated by forensic psychiatric examination.	There was a difference in gene frequency between offenders and non-offenders among heroin-dependent subjects. The 9–9 genotype increases risk of irritability and direct aggressiveness more than 6–9 times compared to the 9–10 genotype. The 9-repeat allele of the DAT polymorphism confers susceptibility to antisocial-violent behavior and aggressiveness, rather than drug dependence
SA and CD	Jain, M. et al Biol Psychiatry 2007 61:1329– 1339	Linkage & identification of candidate genes	18 extended and multigenerational families consisting of 616 members in Columbia (identified via proband children with ADHD diagnosis)	Structured Diagnostic Interviews and the Composite International Diagnostic Interview (CIDI) and the Disruptive Behavior Disorder module from the Diagnostic Interview for Children and Adolescents	Strong linkages among ADHD and ODD, ADHD and CD, ODD and CD, and CD and alcohol abuse/dependence - major genes underlie a broad behavioral phenotype that manifest as ADHD, disruptive behaviors (CD and ODD) and alcohol abuse or dependence. Evidence of linkage for comorbid ADHD phenotypes to loci: 8q24, 2p21-22.3, 5p13.1- p13.3, 12p11.23-13.3, 8q15, 14q21.1-22.2.
SA and CD	Corley, RP et al. 2008. Drug and Alcohol Dependenc e 96: 90–98.	Single nucleotide polymorphism (SNP) association from a targeted gene SNP assay (SNP chip)-- designed to assay 1500 SNPs across 50 candidate genes	231 primarily Caucasian male probands in treatment with antisocial drug dependence and matched controls	CIDI-SAM and DISC-IV or DIS	Two genes, CHRNA2 and OPRM1, each probed with multiple SNPs, emerged as plausible candidates for a genetic role in antisocial drug dependence after gene-based permutation testing.
ALC and DEP	Nurnberger, JI et al 2001 Am J Psychiatry 158:718–724	linkage analyses & identification of candidate genes	Cases: Families with 2 additional alcoholic members. Control families: population- based. Initial = 987 individuals (105 families); Replication = 1295 individuals (157 families)	Probands and all available first-degree relatives were interviewed using SSAGA for DSM-III-R.	Peak lod scores for alcoholism OR depression on chromosome 1, 2, 6, and 16. Peak Lod score for comorbid alcoholism and depression was located on chromosome 2 for the replication and combined data sets (score 4.12, 2.16 respectively).
ALC and DEP	Terayama, HT. 2003 Acta Neuropsychi atrica 15:129–132	Candidate gene frequency: human serotonin 2A receptor (5-HTR2A) polymorphism	80 patients with mood disorders, 50 patients with schizophrenia, 41 patients with alcohol dependence. 112 healthy controls from medical staff. All subjects were Japanese.	A psychiatrist and a psychologist conducted clinical interviews and rated participants using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia.	5-HTR2A polymorphism does not seem be associated with susceptibility to schizophrenia, mood disorders, or alcohol dependency.
ALC and DEP	Marques, FZC et al 2006 Psychiatric Genetics 16(3): 125– 131	Candidate gene: serotonin transporter 5-HTTLPR	114 male Brazilian patients of European descent with alcohol dependence and 218 controls from a European Brazilian blood donor bank	DSM-III-R Criteria for alcohol dependence determined using the SSAGA.	ALC patients with comorbid MDD, drug abuse, and nicotine dependence presented higher frequency of the S allele than pure ALC patients. ALC patients with comorbid MDD and drug abuse also had higher frequencies of the S-allele than controls.
ALC and DEP	Szcezepanki ewicz A et al. 2007. Alcohol & Alcoholism 42(2): 70– 74.	Candidate genes: one SNP for each dopamine receptor gene 1–4	317 patients with bipolar disorder, including 42 with alcohol abuse. 350 control subjects.	Interviews with at least two psychiatrists, using the structured clinical interview for DSM-IV Axis 1 disorders (SCID)	Found no association of any of the analyzed dopamine gene polymorphisms with comorbid alcohol abuse in bipolar patients, compared to controls.
ALC and ANX	Young, RM et al. 2002. Alcohol & Alcoholism 37:451–456.	Candidate genes: Taq I A alleles (A1 and A2) of the D2 dopamine receptor (DRD2) gene	91 Caucasian veterans in the Australian armed forces, hospitalized for PTSD and 51 controls, recruited from Brisbane hospitals	Mississippi Scale for Combat-Related Posttraumatic Stress Disorder. Patients also had a psychiatric history taken or were assessed by a clinical nurse.	DRD2 A1 allelic frequency was significantly higher among the harmful drinkers with PTSD (27.6%) than in the non-harmful drinkers with PTSD (14.2%) and than among the controls (6.9%).
ALC, DEP and ANX	Huang, SY et al. 2004. Alcoholism-- Clinical and Experimenta l Research 28(3): 374– 384.	Candidate genes: dopamine D2 receptor (DRD2) gene, alcohol dehydrogenase 1B (ADH1B), and aldehyde dehydrogenase (ALDH2) genes	Han Chinese subjects: 71 had pure alcohol dependence, 113 had alcohol dependence and anxiety-depression and 129 only had anxiety-depression. 152 were normal controls.	Chinese version of the modified Schedule of Affective Disorders and Schizophrenia-Lifetime	The DRD2 gene was not associated with pure alcohol dependence or ANX/DEP, but was associated with ANX/DEP ALC. Furthermore, the association between the DRD2 gene and ANX/DEP ALC was shown to be under the stratification of the ALDH2*1/*1 and ADH1B*1/*2 genotypes.
ALC, DEP and ANX	Lin, S. et al Progress in Neuro-Psychopharmacology & Biological Psychiatry 2007 31:1526– 1534.	Candidate genes: dopamine D2 receptor (DRD2), serotonin transporter promoter region (5-HTTLPR) gene	46 alcohol dependents and 87 ANX/DEP ALC recruited from two hospitals in Taipei, Taiwan. 57 individuals without history or diagnosis of ALC recruited from the community.	Modified Schedule of Affective Disorder. The Tridimensional Personality Questionnaire (TPQ) measured personality traits (novelty-seeking (NS) and harm- avoidance (HA))	ANX/DEP ALC are characterized by higher NS and HA scores; NS was elevated only in ANX/DEP ALC patients with the DRD2 Taq1 A1 allele and in those with the 5-HTTLPR S/S genotype, while HA was elevated only in ANX/DEP ALC samples carrying 5-HTTLPR S/L or L/L genotype.
ALC, DEP and ANX	Huang, SY et al. 2007. Journal of Psychiatry & Neuroscienc e 32(3): 185–192.	Candidate genes: MAOA polymorphisms and dopamine DRD2 receptor gene	427 Han Chinese men (201 control subjects and 226 with alcoholism—108 with pure alcohol dependence (ALC) and 118 with alcohol dependence and anxiety, depression or both (ANX/DEP ALC).	Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime..	The genetic variant of the DRD2 gene was only associated with the ANX/DEP ALC phenotype, and the genetic variant of the MAOA gene was associated with pure ALC. Subjects carrying the MAOA 3-repeat allele and genotype A1/A1 of the DRD2 were 3.48 times (95% confidence interval = 1.47–8.25) more likely to be ANX/DEP ALC than the subjects carrying the MAOA 3– repeat allele and DRD2 A2/A2 genotype.
DEP and ANX	Rowe, DC et al 1998 Behavior Genetics 28(3):218– 225	Candidate gene frequencies (transmission disequilibrium): dopamine transporter (DAT1)	Clinic-referred cases comprise 125 families and controls 53 families, mostly male (83%). From Tucson.	Parents children’s' behavioral problems using the Emory Diagnostic Rating Scale (EDRS).	Symptoms of all eight disorders increased with a greater number of 10-repeat DAT1 alleles. Three disorders show association between- and within- families: (GAD), social phobia, and Tourette's disorder. This suggests that DAT1 makes a contribution to GAD and social phobia that is independent of its contribution to ADHD.
DEP and ANX	Camp, NJ. American Journal of Medical Genetics Part B 2005 135B, 85— 93(115)	Genome-wide linkage analyses	87 large, extended Utah pedigrees. Prospective participants needed to have a family history consisting of ≥3 family members with MDD	The brief screen for psychopathology (BSP) was developed by study staff, as an adaptation to the CIDI.	Evidence for linkage on chromosomes: 3centr (dominant, MDD-recurrent or anxiety), 7p (dominant, MDD-RE or anxiety), and 18q (dominant, MDD-RE and anxiety). Best evidence for 3p12.3-q12.3 (accepted locus for panic disorder, agoraphobia, neuroticism) and 18q21.33-q22.2 (accepted locus for bipolar disorder).
DEP and ANX	Maron, E. 2005 Psychiatric Genetics 15(1):17–24	haplotype analyses of 21 candidate genes: serotonin, cholecystokinin, dopamine, and opioid neurotransmitter systems	127 patients with PD (60 PD-comorbid, 42 PD-pure)and 146 healthy control subjects from Tartu, Estonia.	Mini International Neuropsychiatric Interview (MINI), substantiated by medical records.	Several polymorphisms in the cholecystokinin, serotonin, and dopamine systems were associated with PD-all (HTRC2C Cys23Ser, HTR1A, CCK2, CCK1 1270C-G polymorphism, DRD4 -1217del-G polymorphism) and/or PD- comorbid (HTR1A, CCK1 receptor 246G-A and 1270C-G polymorphisms, CCK gene haplotype -45T/1270G) phenotypes, while pure PD was associated only with the HTR2A receptor and DRD1 receptor polymorphisms.
DEP and ANX	Lawford, BR. et al 2006. European Psychiatry 21: 180–185.	Candidate gene frequency: A1 allele of the D2 Dopamine receptor (DRD2)	57 untreated Caucasian Vietnam veterans with PTSD in Australia.	PTSD diagnosed by psychiatrist according to DSM-IV. For other psychopathologies, participants were Interviewed using the General Health Questionnaire-28 (GHQ).	Participants with the DRD2 A1 allele had higher scores for anxiety/insomnia, social dysfunction, and depression. Cluster analysis identified 2 groups: high-psychopathology (comorbid somatic, anxiety/insomnia, social dysfunction, depression) and a low-psychopathology cluster. DRD2 A1 allele veterans compared to those without this allele were more likely to be found in the high than in the low psychopathology cluster group.
DEP and ANX	Wray, NR. Et al 2007 Arch Gen Psychiatry 64:318–326	6 SNPS from the PLXNA2 gene	Study twins selected according to extreme concordant or discordant neuroticism scores from a Australian population cohort of 18742 twins and their siblings. Total N=624 individuals.	Composite International Diagnostic Interview (CIDI), the 23- item Neuroticism scale of the revised Eysenck Personality Questionnaire, and the Kessler Psychological Distress Scale.	There was evidence of an allelic association between one SNP (rs2478813) of PLXNA2 and ANX, DEP, neuroticism and psychological distress. Individuals who are comorbid for anxiety may drive the association of rs2478813 with depression, neuroticism, and psychological distress.
ALC, CD, DEP and ANX	Schmidt, LG et al. 2000. Journal of Neural Transmissio n 107:681– 689.	Candidate genes: functional 30-bp repeat polymorphism in the promoter region of the MAOA gene [variation in the number of repeats (3– 5) of the MAOA gene- linked polymorphic region (MAOA-LPR)]	298 male alcohol- dependent patients of German descent, of whom 59 also exhibited an antisocial disorder and 31 had an anxious- depressive personality disorder, plus 182 male and 180 female controls, derived from a sample of healthy volunteers.	Substance Abuse Section of the Composite International Diagnostic Interview, while psychiatric comorbidity was diagnosed according to DSM IV criteria--final diagnoses were made based on information from a clinical interview by trained clinicians	Among males, the frequency of the low-activity 3-repeat MAOA genotype was significantly higher in antisocial alcoholics than in controls. Among male alcoholics, a significantly lower frequency of the 3-repeat allele was found in anxious-depressive patients compared to antisocial subjects. In females, no significant differences in genotype frequencies of alcoholic subtypes and controls, but there was a trend of fewer genotypes with a 3-repeat allele in the anxious-depressive subgroup compared to female alcoholics with no other diagnoses.