Project Among African Americans to Explore Risk for Schizophrenia (PAARTNERS)

1. Project Among African Americans to Explore Risk for Schizophrenia (PAARTNERS) Neurocognitive Functioning in Probands and Their Biological Relatives Monica E. Calkins, University of Pennsylvania Ping Tepper, University of Pittsburgh J. Daniel Ragland, University of California, Davis Raquel E. Gur, University of Pennsylvania Ruben C. Gur, University of Pennsylvania Bernie Devlin, University of Pittsburgh Robert M. Savage, University of Alabama, Birmingham Muktar Aliyu, University of Alabama, Birmingham L. Dianne Bradford, Morehouse School of Medicine Neil Edwards, University of Tennessee Joseph Kwentus, University of Mississippi Paul D. Lyons, University of Virginia Joseph P. McEvoy, Duke University Vishwajit Nimgaonkar, University of Pittsburgh Al B. Santos, Medical University of South Carolina Rodney C.P. Go, University of Alabama

2. AIMS of the NIMH-funded multi-site PAARTNERS project • Recruit and assess African-American families containing at least one primary proband diagnosed with schizophrenia (SZ) or schizoaffective disorder (SZA) • Perform genome scan to detect regions potentially harboring liability genes for SZ • Evaluate heritability of neurocognitive phenotypes and their relationships to clinical phenotypes • Perform multipoint Quantitative Trait Locus (QTL) linkage analyses using the endophenotypes • Establish a publicly accessible resource of data per National Institute of Mental Health (NIMH) Human Genetics Initiative guidelines.

3. PAARTNERS METHODS:Overview • Family recruitment (n=631 families) • Affected sibling pairs (ASPs) (n=82): Proband plus at least one sibling diagnosed with SZ or SZA • TRIOs (n=505): proband plus either two parents or at least one sibling for every unavailable parent. • Multiplex (MP) (n=44): proband plus one or more affected first-degree relatives, plus minimum of 8 additional first- to fourth-degree relatives • (Community controls added later in the study) • Standardized clinical and computerized neurocognitive assessment • Data stored and organized at central administrative site (UAB) • 8-Site Collaboration • University of Alabama at Birmingham • Morehouse School of Medicine • Duke University • University of Mississippi Medical Center • Medical University of South Carolina • University of Pennsylvania • University of Pittsburgh • University of Tennessee Behavioral Health Center, Memphis

4. PAARTNERS Assessment Diagnostic Assessment Neurocognitive Assessment • Diagnostic Interview for Genetic Studies (DIGS) and embedded instruments • Family Interview for Genetic Studies (FIGS) • Medical Records • Narrative Summary • Best Estimate Final DSM-IV (consensus) Diagnoses • Computerized Neurocognitive Battery (CNB; Gur et al. 2001) • Laptop administered • Direct data downloading to central repository • Automated scoring • Quality reviewed • 14 tasks to assess 10 neurocognitive domains • Separate indices of accuracy and speed DNA Sample • NIMH • UAB

5. Computerized Neurocognitive Battery (CNB) • Abstraction and Mental Flexibility (ABF) • Abstraction Inhibition and Working Memory Task(Glahn et al. 2000) • Penn Conditional Exclusion Test(Kurtz et al. 2004) • Attention (ATT) • Letter-n-Back, 0-back (Ragland et al. 2002) • Penn Continuous Performance Test-Number and Letter Version(Kurtz et al. 2001) • Working Memory (WM) • Letter-n-Back, 1- and 2-back(Ragland et al. 2002) • Verbal Memory (VMEM) • Computerized Penn Word Memory Test(Gur et al. 1993) • Penn List Learning Task • Face Memory (FMEM) • Penn Face Memory Test (Gur et al. 1993) • Spatial Memory (SMEM) • Visual Object Learning Test (Glahn et al. 1997) • Language (LAN) • Penn Verbal Reasoning Test (Gur et al. 1987) • Spatial Processing (SPA) • Computerized Judgment of Line Orientation(Gur et al. 2001) • Sensori-motor Dexterity (S-M) • Computerized Finger-Tapping Task • Motor Praxis Test • Emotion Processing (EMO) • Penn Emotion Recognition Test (Kohler et al. 2003) • Penn Emotion Discrimination Task(Erwin et al. 1992)

6. Rationale and Hypotheses of Current Report Rationale Hypotheses • Much evidence supports neurocognitive impairment in schizophrenia (e.g., Aleman et al. 1999, Gur et al. 2007), but little is known about neurocognitive function in African-American schizophrenia families. • Neurocognitive performance in African-American families will parallel performance observed in other family studies. • Among family members of schizophrenia patients, individuals with schizophrenia will exhibit greater neurocognitive impairment than individuals with other (and no) disorders. • In schizophrenia family studies of neurocognition, relationship to comorbid psychopathology not well delineated (e.g., Snitz et al. 2006; Hoff et al. 2005), despite that some neurocognitive impairments are observed in other diagnostic groups (e.g., mood disorders). • Substantial heritability of some aspects of neurocognitive functioning observed in schizophrenia (e.g. Gur et al. 2007), but no studies have specifically examined heritability in African-American families • Neurocognitive abilities implicated as candidate endophenotypes in schizophrenia will be substantially heritable in African-American families.

7. Statistical Approach • Group Differences: Generalized Estimating Equation (GEE) to account for relatedness among family members • Hierarchical Groups • Schizophrenia/Schizoaffective (SCZ/SA) • Major Depressive Disorder (MDD) • Bipolar Disorder (BP) • Substance Related Disorders (SRD) • Other Axis I and II (OTH) • Unaffected (UNAF) • Dichotomous Coded Groups • Each individual assigned a code (1=diagnosis given, 0=otherwise) for each of 10 diagnoses • Heritability: Estimated using restricted maximum likelihood (REML) (AIREMLF90)

8. Current Sample (n = 1535) Demographic Characteristics 1The majority of relatives are first-degree. N other degree = 160

9. Hierarchical Groups: Accuracy SCZ/SA, MDD, BP, UNAF SCZ/SA, SRD, OTH, UNAF Covaried for age and sex.

10. Hierarchical Groups: Speed SCZ/SA, MDD, BP, UNAF SCZ/SA, SRD, OTH, UNAF Covaried for age and sex.

11. Dichotomous Coding: Accuracy by Diagnosis • Schizophrenia (SCZ) • Schizoaffective- Depressed (SAD) • Schizoaffective- Bipolar (SAB) • Psychotic Disorders (PS) • Substance Related Disorders (DRG) • “Organic” Psychotic Disorders (OPSY) • Other Axis I and II (OTH) • Bipolar Disorder (BPD) • Major Depressive Disorder (MDD) • Other Mood Disorders (OMD)

12. Dichotomous Coding:Speed by Diagnosis • Schizophrenia (SCZ) • Schizoaffective- Depressed (SAD) • Schizoaffective- Bipolar (SAB) • Major Depressive Disorder (MDD) • Bipolar Disorder (BP) • Substance Related Disorders (SRD) • Other Mood Disorders (OMD) • Psychotic Disorders (PSY) • “Organic” Psychotic Disorders (OPSY) • Other Axis I and II (OTH)

13. Heritability: Accuracy

14. Heritability: Speed

15. Heritability:Multiplex, Multigenerational Investigation

16. Conclusions • PAARTNERS has recruited and assessed the largest sample of African American schizophrenia families to date • Neurocognitive function in African American schizophrenia families parallels performance observed in other family studies • Family members with schizophrenia exhibit reduced accuracy and speed in most neurocognitive domains compared to unaffected relatives and those with other disorders • The heritability of most neurocognitive abilities is substantial (highest for ABF, VMEM and SPA accuracy, and ATT speed) and generally comparable to that observed in European American families • Results support the use of neurocognitive abilities as candidate endophenotypes in African American families

17. Acknowledgments • RO1 MH66006 (L. Dianne Bradford) • R01 MH66278 (Bernie Devlin) • R01 MH066049 (Neil Edwards) • R01MH66181-03 (Rodney Go) • R01 MH66121 (Raquel Gur) • R01 MH066005 (Joseph Kwentus) • R01 MH66050 (Joseph McEvoy) • R01MH66263 (Vishwajit Nimgaonkar) • R01 MH66004 (Alberto Santos)