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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Am J Psychiatry. Author manuscript; available in PMC 2011 June 14.
Published in final edited form as:
PMCID: PMC3114558
NIHMSID: NIHMS273623

Prevalence of Incompletely Penetrant Huntington’s Disease Alleles Among Individuals With Major Depressive Disorder

Abstract

Objective

Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington’s disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established.

Method

This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression.

Results

CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats.

Conclusions

In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles.

Huntington’s disease is a progressive, dominantly inherited neurodegenerative disorder characterized by motor and cognitive symptoms. It is caused by a mutation in one copy of the Huntingtin (HTT) gene, comprising an expanded version of a polymorphic CAG trinucleotide repeat (1, 2). Normal chromosomes possess CAG alleles ranging from six to 34 units. Repeat expansions of 40 units or more are fully penetrant and lead to onset of overt clinical symptoms, with age at onset inversely correlated with the repeat length, whereas repeats of 36–39 units may exhibit reduced penetrance (3). Recent reports underscore the prevalence of psychiatric symptoms in Huntington’s disease as well, particularly depression, irritability, and impaired impulse control, which may be present early in the disease course (4) or even precede the characteristic chorea by 10 years or more (5). In one study of presymptomatic Huntington’s disease repeat carriers, for example, study subjects displayed greater levels of irritability as well as cognitive symptoms (6).

Studies of the pathophysiology of major depressive disorder have revealed associated changes in striatal perfusion at rest (7) and during reward processing (810) and learning tasks (11). Recently, direct stimulation of striatum has shown evidence of efficacy in difficult-to-treat major depression (12). More broadly, high rates of depression are observed across basal ganglia diseases (13, 14), including caudate stroke (15). Likewise, a growing body of evidence suggests glutamatergic abnormalities in major depression (16), and glutamatergic drugs may exhibit antidepressant effects (17). Thus, both in clinical presentation and in pathophysiology, similarities between Huntington’s disease and major depressive disorder are apparent.

Recent studies suggest that a small but definable proportion of apparent cases of psychiatric disorders such as schizophrenia may be accounted for by rare copy-number variations. One example is the 22q11 deletion associated with velocardiofacial syndrome, present in multiple studies of clinical samples of schizophrenia patients (18, 19). While it is known that even “presymptomatic” carriers of the Huntington’s disease risk allele may exhibit mood symptoms, it has been assumed that carriers would still be extremely rare in clinical populations with major depression. To our knowledge, only one small study has examined the HTT CAG repeat in patients diagnosed with major depression, and it found no expanded alleles among 16 patients (20). Thus, from a clinical perspective, it is unknown how commonly individuals presenting with major depression carry risk alleles for Huntington’s disease.

To better characterize the prevalence of HTT CAG repeats in clinical populations with major depression, we first examined HTT CAG repeat length in two cohorts of affected individuals, including one drawn from the Sequential Treatment Alternatives to Relieve Depression (STAR*D) cohort, and in comparison subjects. We hypothesized that expanded HTT alleles would be over-represented among individuals with major depression relative to comparison subjects. To attempt to replicate initial findings, we then examined repeat length in a third cohort of patients with major depression and comparison subjects.

Method

Clinical Cohort 1

As part of a study of genetic influences on neuroimaging phenotypes, the Phenotype Genotype Project (21), three groups of individuals were recruited through newspaper advertisements or referrals from psychiatric clinics: individuals with major depressive disorder, individuals with cocaine use disorders, and a healthy comparison group matched for age, sex, education, and ethnicity. All participants underwent a clinical interview that included the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID; 22). Race was determined by self-identification on a standardized form (23). Participants also completed the Inventory of Depressive Symptomatology–Self Report (24, 25) and the Edinburgh Handedness Inventory (26). Participants had to be 18–55 years of age and have no current or lifetime DSM-IV axis I disorder or major medical illness known to influence brain structure or function, including neurologic disease, HIV, and hepatitis C. All participants provided written informed consent, and the protocol was approved by the institutional review board of Massachusetts General Hospital. In the major depression group (N=34), the mean age was 38.4 years (SD=11.2), all were Caucasian, and 47.1% were women. In the comparison group (N=74), the mean age was 34.8 years (SD=11.9), all were Caucasian, and 46.0% were women.

Clinical Cohort 2

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was a multicenter study conducted in the United States with more than 4,000 individuals who presented to primary or specialty care clinics for treatment of depression. Details of the STAR*D protocol and clinical results have been presented previously (27, 28). DNA was collected for 1,932 of the participants and was made available to us in an anonymized form by the National Institute of Mental Health; DNA from 1,493 self-reported Caucasian participants was used in the present analysis. In this group, 61.0% were women, and the mean age was 42.7 years (SD=13.5). The STAR*D clinical and genetics protocols were approved by the institutional review boards of participating institutions. Because the DNA was provided in anonymized form, the Massachusetts General Hospital institutional review board determined that the study protocol did not represent human subjects research.

Determining an appropriate comparison group for this study was complicated by the late onset of Huntington’s disease and by the fact that, to our knowledge, the HTT CAG repeat has not been examined in large non-Huntington’s cohorts. Therefore, because Huntington’s disease is a relatively uncommon dominantly inherited disorder (1 in 10,000), we used as an initial comparator for this cohort CAG repeat frequency on the second chromosome (i.e., the one with the shorter repeat) in large cohorts of patients with Huntington’s disease (N=4,007), which should reflect the underlying population distribution of the HTT CAG allele.

Clinical Cohort 3

Patients with a clinical diagnosis of major depression were recruited from consecutive admissions to the inpatient unit of the Department of Psychiatry and Psychotherapy of the University of Bonn, Germany. DSM-IV diagnosis was made by psychiatrists or psychologists applying a consensus best-estimate procedure based on all available information, including a structured interview (the SCID), medical records, and family informants when available. All patients (N=601) included in the study were of Caucasian ancestry, based on self-reported information about grandparents. The mean age at interview was 47.4 years (SD=13.8), and the mean age at onset of major depression, defined as when DSM-IV criteria were fulfilled for the first time, was 36.4 years (SD=13.2). The cohort was 63.7% women.

The comparison sample (N=1,339) was recruited within the framework of the German National Research Project in the region of Bonn to serve as a comparison sample for genetic studies of several neuropsychiatric phenotypes. Population-based recruitment was performed in collaboration with the local census bureau. Participants were evaluated by an experienced psychiatrist and screened for neurological and psychiatric disorders with a structured questionnaire. The mean age at interview was 47.8 years (SD=15.3), and the cohort was 52.2% women.

All participants provided written informed consent. All participants also consented to transfer of DNA and phenotypic data in an anonymized fashion to other research groups. Protocols and procedures were approved by the local ethics committees.

Molecular Methods

HTT CAG repeat allele sizes were determined by polymerase chain reaction (PCR) using an assay that does not include the adjacent proline (CCG) repeat and that is a modification of the method reported by Warner and colleagues (29). HTT CAG repeat sizes were determined by using a fluorescently labeled/ tailed primer pair, CAG1-6FAM-ATGAAGGCCTTCGAGTCCCT-CAAGTCCTTC and CAG2-GGCGGTGGCGGCTGTTGCTGCT-GCTGCTGC. The PCR conditions were as follows: 80 ng of genomic DNA, 1.25 mmol MgCl2, 1X Buffer II (Applied Biosystems), 0.5 U AmpliTaq Gold (Applied Biosystems), 0.125 μmol each primer, 0.25 mmol deoxyribonucleotide triphosphate, and 12% dimethyl sulfoxide in a 10 μL reaction. The cycling conditions for the reaction were as follows: initial denaturation at 94°C for 4 minutes, followed by 35 cycles of denaturation at 94°C for 30 seconds, annealing at 65°C for 30 seconds, extension at 72°C for 45 seconds, and a final extension of 10 minutes at 72°C. The PCR products were run on an Applied Biosystems 3730XL DNA Analyzer with GeneScan500 LIZ (Applied Biosystems) as the internal size standard. The data were analyzed with GeneMapper v3.7 (Applied Biosystems), and the sizes were converted to CAG repeat number based on comparison to known CAG repeat number standards.

Analysis

We defined HTT risk alleles (completely or incompletely penetrant) a priori as those with a length ≥36, the threshold at which Huntington’s disease risk appears to emerge (3). Fisher’s exact test was used to compare frequency of HTT risk alleles among case and comparison subjects.

Power for an alpha level of 0.05 was estimated by simulation using the PLINK software tool set (30), assuming a genotype relative risk of 6 and a minor allele frequency of 0.001, using Fisher’s exact test. Power to detect association under these conditions was 23.5%. Stata 10.0 (Stata Corp., College Station, Tex.) was used for all analyses.

Results

In cohort 1, two of 68 chromosomes from patients with major depression had HTT CAG repeat allele sizes ≥36 (lengths of 36 and 37), compared with none of 148 chromosomes from participants in the comparison group (Fisher’s exact test, p=0.098). In cohort 2, a total of four alleles of 36 repeats or greater were observed (lengths of 36, 37, 38, and 42) among 2,986 chromosomes from depressed subjects, compared with none of 4,007 control chromosomes (Fisher’s exact test p=0.006). Figure 1 shows the distribution of HTT allele lengths among patients with major depression and healthy comparison subjects in this second cohort.

FIGURE 1
Distribution of HTT Allele Length in 4,007 Healthy Comparison Subjects and 2,986 Patients With Major Depression

In the replication cohort (cohort 3), one expanded allele (N=38) was identified among 1,202 chromosomes from patients with major depression, and none of 2,678 chromosomes from comparison subjects (Fisher’s exact test, p=0.31). For the three cohorts combined, we observed 7/4,256 expanded alleles compared with 0/6,833 among comparison chromosomes (Fisher’s exact test, p=0.001).

Table 1 compares demographic and clinical features for four participants with allele lengths ≥36 with the remainder of cohort 2. No pattern of sociodemographic or clinical features was apparent. Of note, the one participant with an allele length of 42 (i.e., in the fully penetrant Huntington’s disease range) showed clinical improvement with citalopram treatment. Structural neuroimaging in 84 participants from cohort 1 (34 with major depression, 50 comparison subjects) indicated that caudate volumes for two individuals with major depression with expanded alleles and for the major depression cohort as a whole were not significantly smaller in volume relative to those of comparison subjects. (The normalized caudate volumes were 0.60 [SD=0.01] for each group; see the data supplement that accompanies the online edition of this article.)

TABLE 1
Clinical and Demographic Characteristics of Participants With Major Depressive Disorder With ≥36 Repeat Alleles (“Expanded”) and Remainder of Cohort

Discussion

We identified seven expanded CAG repeats among patients with major depression and none among healthy comparison subjects after examining a total of 11,089 chromosomes. While the distribution of HTT CAG allele lengths in unselected populations has not been well established, our results suggest that low-end Huntington’s disease-associated alleles are overrepresented among individuals diagnosed with major depression. Specifically, our results would estimate that ~7/2,128, or 3.3 in 1,000, individuals diagnosed with major depression carry an expanded HTT CAG allele (95% confidence interval=0.9–5.7).

The most straightforward interpretation of our results would suggest that all of these individuals will ultimately develop Huntington’s disease with time and that the depressive symptoms simply represent a prodromal presentation, as other studies have suggested (5, 6). Indeed, all of the patients with major depression reported on here are below the predicted age at onset of Huntington’s disease based on repeat number (31, 32). This interpretation would suggest a parallel with the 22q11 deletion associated with velocardiofacial syndrome but also seen in clinical samples of patients previously diagnosed with apparent schizophrenia (18, 19). While one could hypothesize some enrichment of expanded Huntington’s disease alleles among individuals with depressive or irritable symptoms, our results indicate a greater-than-expected prevalence among individuals diagnosed with major depression. They would underscore the importance of inquiring about family history of movement disorder and, where indicated, performing a careful neurologic examination in individuals with depressive symptoms.

Alternatively, our results may shed light on the phenotype corresponding to incompletely penetrant alleles. Molecular studies indicate that the CAG repeat length affects mitochondrial ADP phosphorylation (33), even for CAG repeat lengths in the intermediate range. However, no clinical phenotype has previously been described for these low-end HTT alleles, except when they cause the overt clinical symptoms of Huntington’s disease. Our results would also be consistent with a model in which incompletely penetrant alleles are associated with risk for presenting with depressive symptoms even if they never lead to the movement disorder characteristic of Huntington’s disease. This hypothesis may merit investigation in presymptomatic Huntington’s disease cohorts. The mean age of individuals with expanded CAG repeats here is more than two decades before the predicted onset age of motor symptoms based on allele length, and thus earlier than psychiatric symptoms are typically reported (31, 32). Notably, data from a Huntington’s disease mouse model suggest that the antidepressant fluoxetine improves depression-like behaviors associated with characteristic Huntington’s disease pathology (34), which might explain the observed benefit of antidepressant treatment in some of the cases identified in our study.

Limitations of this study include the absence of a neurologic examination of sufficient scope to rule out Huntington’s disease motor symptoms in cohort 2 and the absence of systematic collection of family history of neurologic diseases in any of the three cohorts. Therefore, we cannot exclude the possibility of unrecognized Huntington’s disease, particularly in cohort 2, although it is important to underscore that for all participants in the depression group, the primary diagnosis was major depressive disorder, and thus individuals with known or suspected Huntington’s disease would not have been enrolled. As DNA was provided to us in an anonymized fashion and recontact with participants was prohibited by the institutional review board, it is impossible to obtain further neurologic examination or longitudinal follow-up data to determine which of these individuals will develop Huntington’s disease motor symptoms. With this limitation in mind, more detailed clinical characterization and longitudinal observations of individuals with HTT CAG alleles in the incompletely penetrant range would be of great value.

We also caution that the power to detect association is limited (~23.5%) even with multiple large cohorts, because the risk variant is rare. For a genome-wide study, the risk of spurious association (i.e., a low posterior probability) would be great under these conditions, as both prior probability for any given locus and power are low. Conversely, in the present study, where only one locus was tested based on a high prior probability of association, the posterior probability would be substantially greater despite modest power. Still, analysis of additional cohorts of patients with major depression and comparison subjects will be important to estimate the risk allele frequency with greater precision.

These results add to a growing body of literature suggesting that major depression is a heterogeneous illness whose presentation overlaps with neurodegenerative disorders. That is, some individuals presenting with a major depressive episode may be prodromal for a neurodegenerative illness. For three of the paradigmatic neurodegenerative disorders—Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease—depressive symptoms may precede other typical disease symptoms, in some cases by a decade or more (5, 6, 35, 36). In Parkinson’s disease, there is evidence of shared disease liability with depression: first-degree relatives of individuals with Parkinson’s disease are at elevated risk for depressive and anxiety disorders (37). Carriers of risk genes for other neurologic disorders believed to affect the basal ganglia, such as DYT1 in idiopathic torsion dystonia, likewise have an elevated risk for recurrent major depression (38). Further studies examining disease risk genes for neurodegenerative disorders, particularly those affecting the basal ganglia, among cohorts with major depression may help to elucidate the pathophysiology underlying depressive symptoms in general. These studies may also help to clarify the utility of further examination for neurologic disorders in patients presenting with a major depressive episode.

Supplementary Material

Supplemental Methods and results

Acknowledgments

Dr. Perlis has received research support, advisory or consulting fees, or speaking fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Elan/Eisai, GlaxoSmithKline, Pfizer, and U.S. Pharmaceuticals Group and has equity holdings in and patents for Concordant Rater Systems, LLC. Dr. Smoller has served as a consultant or adviser to, or received honoraria from, Enterprise Analysis Corp., Eli Lilly, Hoffman-La Roche, MPM Capital, and Roche Diagnostics Corporation. Dr. Fava has received research support or advisory, consulting, or speaking fees from Abbott Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, Bayer AG, Biovail Pharmaceuticals, Boehringer-Ingelheim, BrainCells, Bristol-Myers Squibb, Cephalon, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, GlaxoSmithKline, Grunenthal GmbH, J& J Pharmaceuticals, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knoll Pharmaceutical Company, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Neuronetics, Novartis, Nutrition 21, Organon, PamLab, Pfizer, Pharmavite, PharmaStar, Roche, Sanofi/Synthelabo, Sepracor, Solvay Pharmaceuticals, Somaxon, Somerset Pharmaceuticals, U.S. Pharmaceuticals Group, and Wyeth-Ayerst; he also has equity holdings in Compellis and MedAvante. The other authors report no financial relationships with commercial interests.

Supported by NIMH grant R01MH086026; the Bowman Family Foundation; a Young Investigator Award from NARSAD and the Sidney R. Baer, Jr., Foundation to Dr. Perlis; grant 14118 from the National Institute on Drug Abuse and the Office of National Drug Control Policy–Counterdrug Technology Assessment Center; grant DABK39-03-C-0098 from the Phenotype Genotype Project in Addiction and Depression; and grant NS16367 from the National Institute of Neurological Disorders and Stroke. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was supported by federal funds from NIMH under contract N01 MH-90003 to the University of Texas Southwestern Medical Center at Dallas (Dr. Rush, principal investigator).

Footnotes

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

References

1. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes (the Huntington’s Disease Collaborative Research Group) Cell. 1993;72:971–983. [PubMed]
2. MacDonald ME, Gines S, Gusella JF, Wheeler VC. Huntington’s disease. Neuromolecular Med. 2003;4:7–20. [PubMed]
3. Semaka A, Creighton S, Warby S, Hayden MR. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clin Genet. 2006;70:283–294. [PubMed]
4. Kirkwood SC, Su JL, Conneally P, Foroud T. Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol. 2001;58:273–278. [PubMed]
5. Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC. Predict-HD Investigators of the Huntington Study Group. Psychiatric symptoms in Huntington’s disease before diagnosis: the Predict-HD study. Biol Psychiatry. 2007;62:1341–1346. [PubMed]
6. Berrios GE, Wagle AC, Markova IS, Wagle SA, Rosser A, Hodges JR. Psychiatric symptoms in neurologically asymptomatic Huntington’s disease gene carriers: a comparison with gene negative at risk subjects. Acta Psychiatr Scand. 2002;105:224–230. [PubMed]
7. Gabbay V, Hess DA, Liu S, Babb JS, Klein RG, Gonen O. Lateralized caudate metabolic abnormalities in adolescent major depressive disorder: a proton MR spectroscopy study. Am J Psychiatry. 2007;164:1881–1889. [PMC free article] [PubMed]
8. Tremblay LK, Naranjo CA, Graham SJ, Herrmann N, Mayberg HS, Hevenor S, Busto UE. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry. 2005;62:1228–1236. [PubMed]
9. Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry. 2005;58:843–853. [PubMed]
10. Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, Dougherty DD, Iosifescu DV, Rauch SL, Fava M. Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry. 2009;166:702–710. [PMC free article] [PubMed]
11. Aizenstein HJ, Butters MA, Figurski JL, Stenger VA, Reynolds CF, 3rd, Carter CS. Prefrontal and striatal activation during sequence learning in geriatric depression. Biol Psychiatry. 2005;58:290–296. [PubMed]
12. Malone DA, Jr, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, Rauch SL, Rasmussen SA, Machado AG, Kubu CS, Tyrka AR, Price LH, Stypulkowski PH, Giftakis JE, Rise MT, Malloy PF, Salloway SP, Greenberg BD. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65:267–275. [PMC free article] [PubMed]
13. Richard IH, McDonald WM. Can “blue” genes affect mood and movement? Neurology. 2004;63:610–611. [PubMed]
14. McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry. 2003;54:363–375. [PubMed]
15. Vataja R, Leppavuori A, Pohjasvaara T, Mantyla R, Aronen HJ, Salonen O, Kaste M, Erkinjuntti T. Poststroke depression and lesion location revisited. J Neuropsychiatry Clin Neurosci. 2004;16:156–162. [PubMed]
16. Pilc A, Chaki S, Nowak G, Witkin JM. Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol. 2008;75:997–1006. [PubMed]
17. Zarate CA, Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–864. [PubMed]
18. Brunet A, Armengol L, Pelaez T, Guillamat R, Valles V, Gabau E, Estivill X, Guitart M. Failure to detect the 22q11.2 duplication syndrome rearrangement among patients with schizophrenia. Behav Brain Funct. 2008;4:10. [PMC free article] [PubMed]
19. Arinami T, Ohtsuki T, Takase K, Shimizu H, Yoshikawa T, Horigome H, Nakayama J, Toru M. Screening for 22q11 deletions in a schizophrenia population. Schizophr Res. 2001;52:167–170. [PubMed]
20. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E, Bird TD, Hayden MR. A worldwide study of the Huntington’s disease mutation: the sensitivity and specificity of measuring CAG repeats. N Engl J Med. 1994;330:1401–1406. [PubMed]
21. Perlis RH, Holt DJ, Smoller JW, Blood AJ, Lee S, Kim BW, Lee MJ, Sun M, Makris N, Kennedy DK, Rooney K, Dougherty DD, Hoge R, Rosenbaum JF, Fava M, Gusella J, Gasic GP, Breiter HC. Phenotype Genotype Project on Addiction and Mood Disorders. Association of a polymorphism near CREB1 with differential aversion processing in the insula of healthy participants. Arch Gen Psychiatry. 2008;65:882–892. [PubMed]
22. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) New York: New York State Psychiatric Institute, Biometrics Research; 1996.
23. Benson V, Marano MA. Current estimates from the National Health Interview Survey, 1995. Vital Health Stat. 1998;10:1–428. [PubMed]
24. Bernstein IH, Rush AJ, Carmody TJ, Woo A, Trivedi MH. Clinical vs self-report versions of the Quick Inventory of Depressive Symptomatology in a public sector sample. J Psychiatr Res. 2007;41:239–246. [PMC free article] [PubMed]
25. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The 16-item Quick Inventory of Depressive Symptomatology (QIDS), Clinician Rating (QIDS-C), and Self-Report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54:573–583. [PubMed]
26. Kirov G, Lowry CA, Stephens M, Oldfield S, O’Donovan MC, Lightman SL, Owen MJ. Screening abcg1, the human homologue of the drosophila white gene, for polymorphisms and association with bipolar affective disorder. Mol Psychiatry. 2001;6:671–677. [PubMed]
27. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M. STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D. implications for clinical practice. Am J Psychiatry. 2006;163:28–40. [PubMed]
28. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz B, Ritz L, Niederehe G. STAR*D Investigators Group. Sequenced Treatment Alternatives to Relieve Depression (STAR*D): rationale and design. Control Clin Trials. 2004;25:118–142. [PubMed]
29. Warner JP, Barron LH, Brock DJ. A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington’s disease chromosomes. Mol Cell Probes. 1993;7:235–239. [PubMed]
30. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK. a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575. [PubMed]
31. Langbehn DR, Philibert R, Caspers KM, Yucuis R, Cadoret RJ. Association of a D2S2944 allele with depression specifically among those with substance abuse or antisocial personality. Drug Alcohol Depend. 2006;83:33–41. [PubMed]
32. Andresen JM, Gayan J, Djousse L, Roberts S, Brocklebank D, Cherny SS, Cardon LR, Gusella JF, MacDonald ME, Myers RH, Housman DE, Wexler NS. The relationship between CAG repeat length and age of onset differs for Huntington’s disease patients with juvenile onset or adult onset. Ann Hum Genet. 2007;71:295–301. [PubMed]
33. Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, MacDonald ME. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet. 2005;14:2871–2880. [PubMed]
34. Grote HE, Bull ND, Howard ML, van Dellen A, Blakemore C, Bartlett PF, Hannan AJ. Cognitive disorders and neurogenesis deficits in Huntington’s disease mice are rescued by fluoxetine. Eur J Neurosci. 2005;22:2081–2088. [PubMed]
35. Green RC, Cupples LA, Kurz A, Auerbach S, Go R, Sadovnick D, Duara R, Kukull WA, Chui H, Edeki T, Griffith PA, Friedland RP, Bachman D, Farrer L. Depression as a risk factor for Alzheimer disease: the MIRAGE study. Arch Neurol. 2003;60:753–759. [PubMed]
36. Reetz K, Lencer R, Steinlechner S, Gaser C, Hagenah J, Buchel C, Petersen D, Kock N, Djarmati A, Siebner HR, Klein C, Binkofski F. Limbic and frontal cortical degeneration is associated with psychiatric symptoms in PINK1 mutation carriers. Biol Psychiatry. 2008;64:241–247. [PubMed]
37. Arabia G, Grossardt BR, Geda YE, Carlin JM, Bower JH, Ahlskog JE, Maraganore DM, Rocca WA. Increased risk of depressive and anxiety disorders in relatives of patients with Parkinson disease. Arch Gen Psychiatry. 2007;64:1385–1392. [PubMed]
38. Heiman GA, Ottman R, Saunders-Pullman RJ, Ozelius LJ, Risch NJ, Bressman SB. Increased risk for recurrent major depression in DYT1 dystonia mutation carriers. Neurology. 2004;63:631–637. [PubMed]