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
AIMS of the NIMH-funded multisite PAARTNERS project
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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.
PAARTNERS METHODS:
Overview
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8-Site Collaboration
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Family recruitment (n=631 families)
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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
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)
PAARTNERS Assessment
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Diagnostic Assessment
Diagnostic Interview for
Genetic Studies (DIGS)
and embedded
instruments
Family Interview for
Genetic Studies (FIGS)
Medical Records
Narrative Summary
Best Estimate Final DSMIV (consensus) Diagnoses
DNA Sample
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NIMH
UAB
Neurocognitive Assessment
 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
Computerized Neurocognitive
Battery (CNB)
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Abstraction and Mental Flexibility
(ABF)
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Abstraction Inhibition and Working
Memory Task (Glahn et al. 2000)
Penn Conditional Exclusion Test
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Attention (ATT)
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Letter-n-Back, 0-back
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Penn Continuous Performance
Test-Number and Letter Version
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Language (LAN)
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Letter-n-Back, 1- and 2-back
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Spatial Processing (SPA)
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Verbal Memory (VMEM)
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Computerized Penn Word Memory
Test (Gur et al. 1993)
Penn List Learning Task
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Computerized Judgment of Line
Orientation (Gur et al. 2001)
Sensori-motor Dexterity (S-M)
(Ragland et al. 2002)
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Penn Verbal Reasoning Test
(Gur et al. 1987)
Working Memory (WM)
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Visual Object Learning Test
(Glahn et al. 1997)
(Kurtz et al. 2001)
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Spatial Memory (SMEM)
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(Ragland et al. 2002)
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Penn Face Memory Test
(Gur et al. 1993)
(Kurtz et al. 2004)
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Face Memory (FMEM)
Computerized Finger-Tapping Task
Motor Praxis Test
Emotion Processing (EMO)
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Penn Emotion Recognition Test
(Kohler et al. 2003)
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Penn Emotion Discrimination Task
(Erwin et al. 1992)
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.
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Neurocognitive performance
in African-American families
will parallel performance
observed in other family
studies.
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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).
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Among family members of
schizophrenia patients,
individuals with schizophrenia
will exhibit greater
neurocognitive impairment
than individuals with other
(and no) disorders.
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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 AfricanAmerican families
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Neurocognitive abilities
implicated as candidate
endophenotypes in
schizophrenia will be
substantially heritable in
African-American families.
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Statistical Approach
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Group Differences: Generalized Estimating
Equation (GEE) to account for relatedness
among family members
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Hierarchical Groups
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Dichotomous Coded Groups
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Schizophrenia/Schizoaffective (SCZ/SA)
Major Depressive Disorder (MDD)
Bipolar Disorder (BP)
Substance Related Disorders (SRD)
Other Axis I and II (OTH)
Unaffected (UNAF)
Each individual assigned a code (1=diagnosis given, 0=otherwise) for each of 10 diagnoses
Heritability: Estimated using restricted maximum
likelihood (REML) (AIREMLF90)
Current Sample (n = 1535)
Demographic Characteristics
Relative1
Diagnosis
N
Age
Mean
(SD)
Sex
M:F
Education
Mean
(SD)
Maternal
Education
Mean (SD)
SCZ/SA
594
39.7
(11.6)
353:244
11.6
(2.2)
11.0
(3.4)
Major Depressive
Disorder
168
45.2
(14.7)
44:124
12.1
(2.5)
10.3
(3.6)
27
41.6
(12.2)
6:21
13.0
(1.7)
11.7
(3.8)
123
42.7
(11.8)
80:43
11.6
(2.1)
11.1
(3.3)
27
47.3
(15.4)
5:22
11.4
(2.3)
8.8
(3.4)
596
46.5
(16.7)
176:420
12.5
(2.7)
10.5
(3.4)
Bipolar Disorder
Substance
Related Disorder
Other Disorder
Unaffected
1The
majority of relatives are first-degree. N other degree = 160
Hierarchical Groups: Accuracy
SCZ/SA, MDD, BP, UNAF
SCZ/SA, SRD, OTH, UNAF
Covaried for age and sex.
Hierarchical Groups: Speed
SCZ/SA, MDD, BP, UNAF
SCZ/SA, SRD, OTH, UNAF
Covaried for age and sex.
Dichotomous Coding:
Accuracy by Diagnosis
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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)
Dichotomous Coding:
Speed by Diagnosis
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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)
Heritability: Accuracy
h2
SE (h2 )
Lower
95%
CI
Upper
95%
CI
1517
1463
0.45
0.18
0.04
0.04
0.39
0.12
0.51
0.24
1533
1526
1396
1515
0.45
0.39
0.31
0.27
0.04
0.04
0.05
0.04
0.39
0.33
0.24
0.20
0.51
0.45
0.37
0.33
1471
1420
1515
0.32
0.47
0.39
0.04
0.05
0.04
0.25
0.40
0.33
0.38
0.53
0.45
Domain
N
ABF
ATT
VMEM
FMEM
WM
SMEM
LAN
SPA
EMO
Heritability: Speed
Domain
N
h2
SE (h2 )
Lower
95%
CI
Upper
95%
CI
ABF
1522
0.38
0.04
0.32
0.44
ATT
1507
0.43
0.04
0.36
0.48
VMEM
1526
0.19
0.04
0.12
0.25
FMEM
1526
0.22
0.04
0.16
0.28
WM
1360
0.12
0.05
0.06
0.19
SMEM
1515
0.23
0.04
0.16
0.29
LAN
1359
0.11
0.04
0.05
0.17
SPA
1389
0.31
0.05
0.24
0.38
SM
1532
0.14
0.04
0.08
0.20
EMO
1515
0.22
0.04
0.16
0.29
Heritability:
Multiplex, Multigenerational Investigation
Conclusions
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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
Acknowledgments
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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)