Project Among African Project Among African Americans to Explore Americans to Explore

Risk for Schizophrenia Risk for Schizophrenia (PAARTNERS)(PAARTNERS)

Monica E. Calkins, University of PennsylvaniaMonica E. Calkins, University of PennsylvaniaPing Tepper, University of PittsburghPing Tepper, University of Pittsburgh

J. Daniel Ragland, University of California, Davis J. Daniel Ragland, University of California, Davis Raquel E. Gur, University of PennsylvaniaRaquel E. Gur, University of PennsylvaniaRuben C. Gur, University of PennsylvaniaRuben C. Gur, University of Pennsylvania

Bernie Devlin, University of PittsburghBernie Devlin, University of PittsburghRobert M. Savage, University of Alabama, Robert M. Savage, University of Alabama,

BirminghamBirminghamMuktar Aliyu, University of Alabama, BirminghamMuktar Aliyu, University of Alabama, Birmingham

Neurocognitive Functioning in Probands and Their Biological Relatives

L. Dianne Bradford, Morehouse School of MedicineL. Dianne Bradford, Morehouse School of MedicineNeil Edwards, University of TennesseeNeil Edwards, University of Tennessee

Joseph Kwentus, University of MississippiJoseph Kwentus, University of MississippiPaul D. Lyons, University of VirginiaPaul D. Lyons, University of VirginiaJoseph P. McEvoy, Duke UniversityJoseph P. McEvoy, Duke University

Vishwajit Nimgaonkar, University of PittsburghVishwajit Nimgaonkar, University of PittsburghAl B. Santos, Medical University of South CarolinaAl B. Santos, Medical University of South Carolina

Rodney C.P. Go, University of Alabama Rodney C.P. Go, University of Alabama

Recruit and assess African-American families containing Recruit and assess African-American families containing at least one primary proband diagnosed with at least one primary proband diagnosed with schizophrenia (SZ) or schizoaffective disorder (SZA)schizophrenia (SZ) or schizoaffective disorder (SZA)

Perform genome scan to detect regions potentially Perform genome scan to detect regions potentially harboring liability genes for SZharboring liability genes for SZ

Evaluate heritability of neurocognitive phenotypes and Evaluate heritability of neurocognitive phenotypes and their relationships to clinical phenotypestheir relationships to clinical phenotypes

Perform multipoint Quantitative Trait Locus (QTL) Perform multipoint Quantitative Trait Locus (QTL) linkage analyses using the endophenotypeslinkage analyses using the endophenotypes

Establish a publicly accessible resource of data per Establish a publicly accessible resource of data per National Institute of Mental Health (NIMH) Human National Institute of Mental Health (NIMH) Human Genetics Initiative guidelines.Genetics Initiative guidelines.

AIMS of the NIMH-funded multi-AIMS of the NIMH-funded multi-site PAARTNERS projectsite PAARTNERS project

PAARTNERS METHODS:PAARTNERS METHODS:OverviewOverview

Family recruitment (n=631 families)Family recruitment (n=631 families) Affected sibling pairs (ASPs) (n=82): Affected sibling pairs (ASPs) (n=82): Proband plus at least one sibling diagnosed Proband plus at least one sibling diagnosed

with SZ or SZAwith SZ or SZA TRIOs (n=505): TRIOs (n=505): proband plus either two parents or at least one sibling for every proband plus either two parents or at least one sibling for every

unavailable parent.unavailable parent. Multiplex (MP) (n=44): Multiplex (MP) (n=44): proband plus one or more affected first-degree relatives, proband plus one or more affected first-degree relatives,

plus minimum of 8 additional first- to fourth-degree relativesplus minimum of 8 additional first- to fourth-degree relatives (Community controls added later in the study)(Community controls added later in the study) Standardized clinical and computerized neurocognitive assessmentStandardized clinical and computerized neurocognitive assessment Data stored and organized at central administrative site (UAB)Data stored and organized at central administrative site (UAB)

8-Site Collaboration8-Site Collaboration University of Alabama at Birmingham University of Alabama at Birmingham Morehouse School of Medicine Morehouse School of Medicine Duke University Duke University University of Mississippi Medical Center University of Mississippi Medical Center Medical University of South Carolina Medical University of South Carolina University of Pennsylvania University of Pennsylvania University of Pittsburgh University of Pittsburgh University of Tennessee Behavioral Health University of Tennessee Behavioral Health

Center, MemphisCenter, Memphis

PAARTNERS AssessmentPAARTNERS Assessment

Diagnostic Interview for Diagnostic Interview for Genetic Studies (DIGS) Genetic Studies (DIGS) and embedded and embedded instrumentsinstruments

Family Interview for Family Interview for Genetic Studies (FIGS)Genetic Studies (FIGS)

Medical RecordsMedical Records Narrative SummaryNarrative Summary Best Estimate Final DSM-Best Estimate Final DSM-

IV (consensus) DiagnosesIV (consensus) Diagnoses

Diagnostic Assessment Neurocognitive Assessment Computerized Computerized

Neurocognitive Battery Neurocognitive Battery (CNB; Gur et al. 2001)(CNB; Gur et al. 2001)

Laptop administeredLaptop administered Direct data downloading to Direct data downloading to

central repositorycentral repository Automated scoringAutomated scoring Quality reviewedQuality reviewed 14 tasks to assess 10 14 tasks to assess 10

neurocognitive domainsneurocognitive domains Separate indices of accuracy Separate indices of accuracy

and speedand speedDNA Sample

NIMHNIMH UABUAB

Computerized Neurocognitive Computerized Neurocognitive Battery (CNB)Battery (CNB)

Abstraction and Mental Flexibility Abstraction and Mental Flexibility (ABF)(ABF)

Abstraction Inhibition and Working Abstraction Inhibition and Working Memory TaskMemory Task (Glahn et al. 2000)(Glahn et al. 2000)

Penn Conditional Exclusion TestPenn Conditional Exclusion Test (Kurtz et al. 2004)(Kurtz et al. 2004)

Attention (ATT)Attention (ATT) Letter-n-Back, 0-backLetter-n-Back, 0-back

(Ragland et al. 2002)(Ragland et al. 2002) Penn Continuous Performance Penn Continuous Performance

Test-Number and Letter VersionTest-Number and Letter Version (Kurtz et al. 2001)(Kurtz et al. 2001)

Working Memory (WM)Working Memory (WM) Letter-n-Back, 1- and 2-backLetter-n-Back, 1- and 2-back

(Ragland et al. 2002)(Ragland et al. 2002) Verbal Memory (VMEM)Verbal Memory (VMEM)

Computerized Penn Word Memory Computerized Penn Word Memory TestTest (Gur et al. 1993)(Gur et al. 1993)

Penn List Learning TaskPenn List Learning Task

Face Memory (FMEM)Face Memory (FMEM) Penn Face Memory TestPenn Face Memory Test

(Gur et al. 1993)(Gur et al. 1993) Spatial Memory (SMEM)Spatial Memory (SMEM)

Visual Object Learning TestVisual Object Learning Test(Glahn et al. 1997)(Glahn et al. 1997)

Language (LAN)Language (LAN) Penn Verbal Reasoning TestPenn Verbal Reasoning Test

(Gur et al. 1987)(Gur et al. 1987) Spatial Processing (SPA)Spatial Processing (SPA)

Computerized Judgment of Line Computerized Judgment of Line OrientationOrientation (Gur et al. 2001)(Gur et al. 2001)

Sensori-motor Dexterity (S-M)Sensori-motor Dexterity (S-M) Computerized Finger-Tapping TaskComputerized Finger-Tapping Task Motor Praxis TestMotor Praxis Test

Emotion Processing (EMO)Emotion Processing (EMO) Penn Emotion Recognition TestPenn Emotion Recognition Test

(Kohler et al. 2003)(Kohler et al. 2003) Penn Emotion Discrimination TaskPenn Emotion Discrimination Task

(Erwin et al. 1992)(Erwin et al. 1992)

Rationale and Hypotheses of Rationale and Hypotheses of Current ReportCurrent Report

Neurocognitive abilities implicated Neurocognitive abilities implicated as candidate endophenotypes in as candidate endophenotypes in schizophrenia will be substantially schizophrenia will be substantially heritable in African-American heritable in African-American families.families.

In schizophrenia family studies of In schizophrenia family studies of neurocognition, relationship to comorbid neurocognition, relationship to comorbid psychopathology not well delineated psychopathology not well delineated (e.g., Snitz et al. 2006; Hoff et al. 2005), (e.g., Snitz et al. 2006; Hoff et al. 2005), despite that some neurocognitive despite that some neurocognitive impairments are observed in other impairments are observed in other diagnostic groups (e.g., mood disorders).diagnostic groups (e.g., mood disorders).

Much evidence supports neurocognitive Much evidence supports neurocognitive impairment in schizophrenia (e.g., impairment in schizophrenia (e.g., Aleman et al. 1999, Gur et al. 2007), but Aleman et al. 1999, Gur et al. 2007), but little is known about neurocognitive little is known about neurocognitive function in African-American function in African-American schizophrenia families.schizophrenia families.

Substantial heritability of some aspects Substantial heritability of some aspects of neurocognitive functioning observed of neurocognitive functioning observed in schizophrenia (e.g. Gur et al. 2007), in schizophrenia (e.g. Gur et al. 2007), but no studies have specifically but no studies have specifically examined heritability in African-examined heritability in African-American families American families

Neurocognitive performance Neurocognitive performance in African-American families in African-American families will parallel performance will parallel performance observed in other family observed in other family studies.studies.

Among family members of Among family members of schizophrenia patients, schizophrenia patients, individuals with schizophrenia individuals with schizophrenia will exhibit greater will exhibit greater neurocognitive impairment than neurocognitive impairment than individuals with other (and no) individuals with other (and no) disorders.disorders.

Rationale Hypotheses

Group Differences:Group Differences: Generalized Estimating Generalized Estimating Equation (GEE) to account for relatedness Equation (GEE) to account for relatedness among family membersamong family members Hierarchical GroupsHierarchical Groups

Schizophrenia/Schizoaffective (SCZ/SA)Schizophrenia/Schizoaffective (SCZ/SA) Major Depressive Disorder (MDD)Major Depressive Disorder (MDD) Bipolar Disorder (BP)Bipolar Disorder (BP) Substance Related Disorders (SRD)Substance Related Disorders (SRD) Other Axis I and II (OTH)Other Axis I and II (OTH) Unaffected (UNAF)Unaffected (UNAF)

Dichotomous Coded GroupsDichotomous Coded Groups Each individual assigned a code (1=diagnosis given, 0=otherwise) for each of 10 diagnosesEach individual assigned a code (1=diagnosis given, 0=otherwise) for each of 10 diagnoses

Statistical ApproachStatistical Approach

Heritability:Heritability: Estimated using restricted maximum Estimated using restricted maximum likelihood (REML) (AIREMLF90)likelihood (REML) (AIREMLF90)

Current Sample (n = 1535) Current Sample (n = 1535) Demographic CharacteristicsDemographic Characteristics

RelativeRelative11 DiagnosisDiagnosis

NN AgeAge

Mean Mean

(SD)(SD)

SexSex

M:FM:F

EducationEducation

Mean Mean

(SD)(SD)

Maternal Maternal EducationEducation

Mean (SD)Mean (SD)

SCZ/SASCZ/SA 594594 39.739.7

(11.6) (11.6)

353:244 353:244 11.611.6

(2.2) (2.2)

11.011.0

(3.4) (3.4)

Major Depressive Major Depressive DisorderDisorder

168168 45.245.2

(14.7) (14.7)

44:124 44:124 12.112.1

(2.5) (2.5)

10.310.3

(3.6) (3.6)

Bipolar Disorder Bipolar Disorder 2727 41.641.6

(12.2) (12.2)

6:21 6:21 13.013.0

(1.7) (1.7)

11.711.7

(3.8) (3.8)

Substance Substance Related DisorderRelated Disorder

123123 42.742.7

(11.8) (11.8)

80:43 80:43 11.611.6

(2.1) (2.1)

11.111.1

(3.3) (3.3)

Other DisorderOther Disorder 2727 47.347.3

(15.4) (15.4)

5:22 5:22 11.411.4

(2.3) (2.3)

8.88.8

(3.4) (3.4)

Unaffected Unaffected 596596 46.546.5

(16.7) (16.7)

176:420 176:420 12.512.5

(2.7) (2.7)

10.510.5

(3.4) (3.4) 1The majority of relatives are first-degree. N other degree = 160

Hierarchical Groups: AccuracyHierarchical Groups: Accuracy

SCZ/SA, MDD, BP, UNAF SCZ/SA, SRD, OTH, UNAF

Covaried for age and sex.

Hierarchical Groups: SpeedHierarchical Groups: Speed

SCZ/SA, MDD, BP, UNAF SCZ/SA, SRD, OTH, UNAF

Covaried for age and sex.

Dichotomous Coding: Dichotomous Coding: Accuracy by DiagnosisAccuracy by Diagnosis

Schizophrenia (SCZ)Schizophrenia (SCZ) Schizoaffective- Depressed (SAD)Schizoaffective- Depressed (SAD) Schizoaffective- Bipolar (SAB)Schizoaffective- Bipolar (SAB) Psychotic Disorders (PS)Psychotic Disorders (PS) Substance Related Disorders (DRG)Substance Related Disorders (DRG) ““Organic” Psychotic Disorders (OPSY)Organic” Psychotic Disorders (OPSY) Other Axis I and II (OTH)Other Axis I and II (OTH) Bipolar Disorder (BPD)Bipolar Disorder (BPD) Major Depressive Disorder (MDD)Major Depressive Disorder (MDD) Other Mood Disorders (OMD)Other Mood Disorders (OMD)

Dichotomous Coding:Dichotomous Coding:Speed by DiagnosisSpeed by Diagnosis

Schizophrenia (SCZ)Schizophrenia (SCZ) Schizoaffective- Depressed (SAD)Schizoaffective- Depressed (SAD) Schizoaffective- Bipolar (SAB)Schizoaffective- Bipolar (SAB) Major Depressive Disorder (MDD)Major Depressive Disorder (MDD) Bipolar Disorder (BP)Bipolar Disorder (BP) Substance Related Disorders (SRD)Substance Related Disorders (SRD) Other Mood Disorders (OMD)Other Mood Disorders (OMD) Psychotic Disorders (PSY)Psychotic Disorders (PSY) ““Organic” Psychotic Disorders (OPSY)Organic” Psychotic Disorders (OPSY) Other Axis I and II (OTH)Other Axis I and II (OTH)

Heritability: AccuracyHeritability: Accuracy

DomainDomain NN hh22 SE (hSE (h2 2 )) Lower Lower 95%95%

CICI

Upper Upper 95%95%

CICI

ABFABF 15171517 0.450.45 0.040.04 0.390.39 0.510.51ATTATT 14631463 0.180.18 0.040.04 0.120.12 0.240.24VMEMVMEM 15331533 0.450.45 0.040.04 0.390.39 0.510.51FMEMFMEM 15261526 0.390.39 0.040.04 0.330.33 0.450.45WMWM 13961396 0.310.31 0.050.05 0.240.24 0.370.37SMEMSMEM 15151515 0.270.27 0.040.04 0.200.20 0.330.33LANLAN 14711471 0.320.32 0.040.04 0.250.25 0.380.38SPASPA 14201420 0.470.47 0.050.05 0.400.40 0.530.53EMOEMO 15151515 0.390.39 0.040.04 0.330.33 0.450.45

Heritability: SpeedHeritability: Speed

DomainDomain NN hh22 SE (hSE (h2 2 )) Lower Lower 95%95%

CICI

Upper Upper 95%95%

CICI

ABFABF 15221522 0.380.38 0.040.04 0.320.32 0.440.44ATTATT 15071507 0.430.43 0.040.04 0.360.36 0.480.48VMEMVMEM 15261526 0.190.19 0.040.04 0.120.12 0.250.25FMEMFMEM 15261526 0.220.22 0.040.04 0.160.16 0.280.28WMWM 13601360 0.120.12 0.050.05 0.060.06 0.190.19SMEMSMEM 15151515 0.230.23 0.040.04 0.160.16 0.290.29LANLAN 13591359 0.110.11 0.040.04 0.050.05 0.170.17SPASPA 13891389 0.310.31 0.050.05 0.240.24 0.380.38SMSM 15321532 0.140.14 0.040.04 0.080.08 0.200.20EMOEMO 15151515 0.220.22 0.040.04 0.160.16 0.290.29

Heritability:Heritability:Multiplex, Multigenerational InvestigationMultiplex, Multigenerational Investigation

PAARTNERS has recruited and assessed the largest PAARTNERS has recruited and assessed the largest sample of African American schizophrenia families to datesample of African American schizophrenia families to date

Neurocognitive function in African American Neurocognitive function in African American schizophrenia families parallels performance observed in schizophrenia families parallels performance observed in other family studiesother family studies

Family members with schizophrenia exhibit reduced Family members with schizophrenia exhibit reduced accuracy and speed in most neurocognitive domains accuracy and speed in most neurocognitive domains compared to unaffected relatives and those with other compared to unaffected relatives and those with other disordersdisorders

The heritability of most neurocognitive abilities is The heritability of most neurocognitive abilities is substantial (highest for ABF, VMEM and SPA accuracy, substantial (highest for ABF, VMEM and SPA accuracy, and ATT speed) and generally comparable to that and ATT speed) and generally comparable to that observed in European American familiesobserved in European American families

Results support the use of neurocognitive abilities as Results support the use of neurocognitive abilities as candidate endophenotypes in African American families candidate endophenotypes in African American families

ConclusionsConclusions

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)

AcknowledgmentsAcknowledgments