A Drama-Major’s guide to genetic epidemiology

1. A Drama-Major’s guide to genetic epidemiology Anna Constantino P.I.’s: ArpanaAgrawal, Ph.D., and Michael Lynskey, Ph.D.

2. Setting the Scene… • 2.5 million deaths/year attributable to harmful use of alcohol • 6.7% of US adult population and 11.2% of 13-18 yr-olds have MDD1 • Suicide has been consistently among top 10 causes of death among10-24 yr-olds in the US2 • 3.7% of US adult population has had serious suicidal ideation3 1 nimh.nih.gov; 2 who.int; 3 nsduhweb.rti.org

3. What’s so special about AUD+SI • Is something special about AUD+SI? • Same as any two co-aggregating disorders? • Higher burden of life events, psychopathology, drug use and increasing severity of suicidality and drinking? • More influenced by heritable factors/genotypes? • Because of heavy drinking or MDD? • Are AUD without SI or SI without AUD associated with risks?

4. My Topic: A.U.D.s and S.I. • Four Subgroups: • -AUD/-SI (Neither; N=2822) • +AUD/-SI (Alcohol Use Disorder Only; N=282) • +SI/-AUD (Suicidal Ideation Only; N=524) • +AUD/+SI (Both; N=160) • Quick facts from the MOAFTS sample (N=3787): • 7.45% had AUD only • 13.84% had S.I. only • 4.22% had both AUD and S.I. • OR for AUD and SI was 3.06 • Note: No AUD includes never drank, light drinkers, no symptoms of AUD.

5. Getting SASsed. • Groups of Covariates that we coded for from the MOAFTS interview: Sociodemographic Characteristics, Life Events, Psychopathology and Drug Use, Suicidality, and Features of Drinking • From the Questionnaire: Max Drinks, Drinking Motives, and Personality Traits. • Ran univariate multinomial logistic regression in STATA (clustering for familial relatedness).

6. Trauma

7. Psychopathology

8. Substance Use

9. Difference between +AUD-SI and –AUD+SI: An example

11. Sources of Variation Genetic factors: 100% MZ, 50% DZ (A2) Family/Shared Environment: 100% MZ and DZ (Assumption of equal environments) (C2) Individual Specific/Unique/Non-shared Environment: 0% MZ or DZ (E2)

12. Univariate Twin Analyses

13. Biology Crash-Course: TPH2

14. More About rs4570625 and TPH2 • Human TPH2 spans 97 kilobases, has 11 exons, and resides on chromosome 12 • Rs4570625 is upstream (5’ UTR/promoter) in a region responsible for gene regulation. • Population MAF is about .208, which is similar to our sample (.21) • Rs4570625 has been shown to be associated with increased amygdala reactivity to emotional stimuli (Brown et al. 2005; Canli et al. 2005) • Various studies have shown differing results for which regions of TPH2 are implicated in psychiatric disorders…

16. rs4570625 • Significant association between our SNP and the comorbid group (OR = 1.98; 95% C.I. 1.02-3.83) • Evidence for a protective effect of our SNP on those with AUD only (significant only at the trend level p=0.07)

17. The Bigger Picture: • Implications for clinicians about how to assess and treat individuals with AUD, SI, or both (for example, history of trauma) • +AUD/+SI seems to be a different type of alcohol dependence from alcohol dependence alone • Interesting association between our SNP and +AUD/+SI

18. Thank You!