Suicide: Genetic Risk Factors

1. Suicide: Genetic Risk Factors Hilary Coon, PhD September 13, 2010

2. Overview • Over 33,000 suicide deaths in the US annually (WISQARS, 2005) • Rocky Mountain states have highest rates; Utah is in the top 10 • Utah State Health Department has classified suicide as an epidemic • Complex interplay of environmental & genetic risk factors

3. Evidence for genetic etiology of suicide • Suicide is familial: relatives have 3 x risk of suicidal acts • Familial risk is independent of psychopathology • Adoption studies: increased risk for biological relatives • Identical twins more concordant for suicidal behavior • Proportion of risk due to genetic factors > 50%

4. Combinations of risk factors • Affective disorders not sufficient risk: may need added risk of impulsive-aggressive personality • In veterans, proposed model: PTSD and major depressive disorder (MDD) => higher suicide risk than either PTSD alone or MDD alone

5. Studies of genetic risk in veterans • Common genetic liability to major depression and PTSD (evidence from males in Vietnam Era Twin registry, over 6,700 members) • Canadian meta-analysis of veterans: PTSD symptoms are heritable; genetic factors also partially explain co-occurrence of other personality traits; gene-environment interactions are likely important

6. How is genetic information used? Find disease mutations by determining DNA variation at many locations in the genome. Close to disease mutation, same pattern of DNA will occur in people affected with the disease. When farther away, there is recombination; trait and same DNA pattern won’t consistently occur with disease .

7. Genetic studies: what do we test? • Variation in DNA: Single Nucleotide Polymorphisms (SNPs) • Occur every 100-200 base pairs • ~3,000,000 SNPs per person, ~12,500 SNPs affect protein function • Many SNPs just random variation, use to see if patterns co-occur with disease

8. Single Nucleotide Polymorphism Chips DNA target sequences on chip; look for specific hybridization to these targets Current costs: For 6,000 SNPs, about $150 per subject; For 1,000,000 SNPs is about $500 per subject

9. Gene Expression Studies • Microarray technology to profile expression of thousands of genes simultaneously (transcriptome) • Differential expression can identify a gene pathway • Expression difference can be due to gene itself or due to upstream factors caused by environment that result in cascade of expression differences • Problems: • tissue used (peripheral cells vs. postmortem brain tissue) • Different molecular platforms, different analytical approaches • Diagnostic differences and control groups

10. Genetic Findings: serotonin pathway • Serotonin: clinical benefit from medication that acts on serotonergicnerotransmission. • Serotonin affected by drugs of abuse, plays a role in many brain functions (mood regulation, sleep, pain perception, blood pressure, hormonal activity). • Low serotonin in CSF of suicide completers

11. Serotonin • Serotonin transporter gene, over 50 studies; not all show significant associations; possible association with violent behavior/impulsivity • Serotonin receptors: HTR1A, HTR1B, HTR2A, again not all studies agree • Genes associated with serotonin pathway: TPH1, TPH2, MAOA, positive and negative findings • Hundreds of studies total, why disagreement? • Different definitions of phenotype • Race/gender differences • True genetic heterogeneity

12. Other pathways • Tyrosine Hydroxylase (TH; dompamine pathway): possible association , mixed results • Dopamine receptors (DRD2, DRD4): specific study showing positive association of DRD2 in veterans with PTSD, some negative studies • Catechol-O-methyltransferase (COMT; degrades dopamine); positive associations with violent suicide or suicide completion • Brain-derived neurotrophic factor (BDNF; differentiation, growth, and survival of neurons); may be interaction with alcohol abuse risk

13. Other gene systems • Angiotensin-converting enzyme (ACE); several recent studies, fairly strong associations • Why test? Hypertensive subjects on ACE inhibitors report well-being and increased work performance; other drugs do not show this • Possible interactions with serotonin (vasoconstriction) • Possible effect on hypothalamic-pituitary-adrenal system (altered in major depression • Lipids and suicide? Low cholesterol may be associated with suicide attempts; several small studies, jury is out

14. Hypothesis: mitochondrial dysfunction • Living at increased elevation creates metabolic stress; individuals susceptible to suicide may lack compensatory mechanisms to overcome this stress • This metabolic stress may be due to mitochondrial dysfunction • Overlap in symptomology between psychiatric and mitochondrial disorders • Mitochondrial dysfunction in bipolar disorder (MRS studies) • Compromised oxidative stress in schizophrenia • mtDNA SNPs associated with SZ, BPD, MDD

15. Pilot data: mitochondrial sequencing • Pilot mitochondrial sequence obtained on 4 suicide cases • - About 25-30 variants per subject - some previously associated with mental illness or altered brain pH. • MT-RNR1 and MT-ND2 genes showed variants in 4/4 subjects, gene previously implicated in schizophrenia (Martorell 2006).

16. MT variants associated with brain pH • Decreased brain pH associated with bipolar (Stork & Renshaw, 2005) • Variant in MT-TL2 gene and variant in MT-ND5 gene in one subject; these genes involved in altered brain pH (Kazuno, 2008) • Variant in MT-ND3 in another subject; this gene associated with brain pH and lithium response in bipolar (Kazuno, 2006) • We now have mitochondrial sequence on 15 more subjects; data analysis in progress

17. DNA: collaboration with OME • Historical samples from early collection: DNA, demographics (N > 1,000) • New data (N = ~300): • 1-year collection starting October 2008 • Extensive phone survey with best current informant covering multiple risk factors • Blood for DNA • Multiple toxicology samples (blood, hair, urine, liver): can test prescription/recreational drugs

19. Link cases through UPDB UPDB: genealogical records of founding Utah pioneers; allowed to use for medical research; death registry, hospital discharge codes.

20. Future directions • Particular mutation(s) may make individuals more/less likely to respond to particular treatments • Particular mutation(s) may make individuals more/less vulnerable to environmental stresses; timing of stress may be important • Ideal: tailor prevention/intervention/treatment to individual genetic vulnerability; is this possible?

21. Utah Suicide Study Team • Doug Gray MD, PI, Dept. of Psychiatry • William McMahon, MD, Chair, Dept. of Psychiatry • Todd Grey, MD, Medical Examiner • Perry Renshaw MD, PhD, Brain Institute • Deborah Yurgelun-Todd, PhD, Brain Institute, MIRECC • Diana Wilkins PhD, Pharmacology and Toxicology Dept. • Reid Robison MD, MBA, Dept. of Psychiatry • Dale Cannon PhD, Dept. of Psychiatry • Michelle Moskos PhD, MHP, Dept of Psychiatry

22. Other Acknowledgements • University of Utah Department of Psychiatry • Utah Office of the Medical Examiner (OME) • Utah Division of Substance Abuse and Mental Health (Mark Payne) • National Alliance on Mental Illness (Utah NAMI) • Intermountain Injury Control Research Center (Mike Dean, MD) • Administrative Office of Juvenile Courts (Ray Wahl, Bruce Thomas) • Marriner Eccles Foundation, and Emma Eccles Foundation • Substance Abuse & Mental Health Services Administration (SAMHSA) • The Utah State Legislature • Primary Children’s Foundation (Edward Clark, MD) • Utah Commission on Criminal and Juvenile Justice • Center for Clinical and Translational Services (previously CRC) • Gary Burlingame PhD, BYU • Utah Department of Health (Violence and Injury Prevention) • Multiple participating Utah Agencies • Parent survivors serving as advisors to our research program

23. Selected References Afifi TO, Asmundson GJ, Taylor S, Jang KL (2010) The role of genes and environment on trauma exposure and posttraumatic stress disorder symptoms: a review of twin studies. ClinPsychol Rev, 30:101-112. Baldessarini RJ, Hennen J (2004) Genetics of suicide: an overview. Harv Rev Psychiat 12:1-13. Bondy B, Buettner, Zill P (2006) Genetics of suicide. Molecular Psychiatry 11:336-351. Brent DA, Mann JJ (2005) Family genetic studies, suicide, and cuicidal behavior. Am J Med Genet. 133C:13-24. Currier D, Mann JJ (2008) Stress, genes, and the biology of suicidal behavior. PsychiatrClin North Am. 31:247-69. Egeland JA, Sussex JN (1985) Suicide and family loading for affective disorders. JAMA 254:915-918. Ernst C, Mechawar N, Turecki G (2009) Suicide neurobiology. ProgNeurobiol 89:315-333. Geigling (2010); Kazuno AA, Munakata K, Mori K, Nanko S, Kunugi H, Nakamura K, Mori N, et al. (2009) Mitochondrial DNA haplogroup analysis in patients with bipolar disorder. Am J Med Genet. 150B:243-247. Kim CD, Seguin M, Therrien N, Riopen G, Chawky N, Sesage AD, Turecki G (2005) Familial aggregation of suicidal behavior: a family study of male suicide completers from the general population. Am J Psychiat 162:1017-1019.

24. References, continued Koenen KC, Fu QJ, Ertel K, Lyons MJ, Eisen SA, True WR, Goldberg J, Tsuang MT (2008) Common genetic liability to major depression and posttraumatic stress disorder in men. J Affect Disord, 105:109-15. Sher L (2009) A model of suicidal behavior in war veterans with posttraumatic mood disorder. Med Hypotheses, 73:215-9. Stork C, Renshaw PF (2005) Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiat 10:900-919. Suicidal Behaviors: Genetic Association Studies Database (SBGAS) from McGill suicide study group http://gmes.mcgill.ca/SBGAS-home.html Wender PH, Seymour SK, Rosenthal D, Schulsinger F, Ortmann J, Lunde I (1986) Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders. Arch Gen Psychiat 43:923-929. WISQARS: Web-based Injury Statistics Query and Reporting System (2005), available from: www.cdc.gov/ncipc/wisqars/default.htm.