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TITLE TEXTAmanda Zheutlin, PhD
Massachusetts General Hospital
PENETRANCE AND PLEIOTROPY OF SCHIZOPHRENIA PRS IN 90,000 PATIENTS
DISCLOSURES
DISCLOSURES▸ Nothing to disclose.
INTRODUCTION
PREDICTING SCHIZOPHRENIA
WHO, 2003; Schoenbaum et al., 2017, Schizophr Bull; Craig et al., 2004, BMJ; Fowler et al., 2009, Early Interv Psychiatry; McGorry et al., 1996, Schizophr Bull; Mihalopoulos et al., 2009, Schizophr Bull; Petersen et al., 2005, BMJ; Srihari et al., 2015, Psychiatr Serv; Fusar-Poli et al., 2017, JAMA Psychiatry
INTRODUCTION
PREDICTING SCHIZOPHRENIAPublic Health
Burden
• Second most costly disease in the U.S.
• Massive increase in mortality
WHO, 2003; Schoenbaum et al., 2017, Schizophr Bull; Craig et al., 2004, BMJ; Fowler et al., 2009, Early Interv Psychiatry; McGorry et al., 1996, Schizophr Bull; Mihalopoulos et al., 2009, Schizophr Bull; Petersen et al., 2005, BMJ; Srihari et al., 2015, Psychiatr Serv; Fusar-Poli et al., 2017, JAMA Psychiatry
INTRODUCTION
PREDICTING SCHIZOPHRENIAPublic Health
Burden
• Second most costly disease in the U.S.
• Massive increase in mortality
Early Intervention
Helps
• Early intervention improves symptoms, quality of life, and engagement in work and school
WHO, 2003; Schoenbaum et al., 2017, Schizophr Bull; Craig et al., 2004, BMJ; Fowler et al., 2009, Early Interv Psychiatry; McGorry et al., 1996, Schizophr Bull; Mihalopoulos et al., 2009, Schizophr Bull; Petersen et al., 2005, BMJ; Srihari et al., 2015, Psychiatr Serv; Fusar-Poli et al., 2017, JAMA Psychiatry
INTRODUCTION
PREDICTING SCHIZOPHRENIAPublic Health
Burden
• Second most costly disease in the U.S.
• Massive increase in mortality
Early Intervention
Helps
• Early intervention improves symptoms, quality of life, and engagement in work and school
WHO, 2003; Schoenbaum et al., 2017, Schizophr Bull; Craig et al., 2004, BMJ; Fowler et al., 2009, Early Interv Psychiatry; McGorry et al., 1996, Schizophr Bull; Mihalopoulos et al., 2009, Schizophr Bull; Petersen et al., 2005, BMJ; Srihari et al., 2015, Psychiatr Serv; Fusar-Poli et al., 2017, JAMA Psychiatry
Poor Risk Detection
• Most patients already in mental health treatment who later develop psychosis are not detected
INTRODUCTION
GENETIC RISK STRATIFICATION
Ripke et al., 2014, Nature; Khera et al., 2018, Nature Genetics
INTRODUCTION
GENETIC RISK STRATIFICATION
Ripke et al., 2014, Nature; Khera et al., 2018, Nature Genetics
INTRODUCTION
GENETIC RISK STRATIFICATION
Ripke et al., 2014, Nature; Khera et al., 2018, Nature Genetics
INTRODUCTION
CLINICAL TRANSLATION
INTRODUCTION
CLINICAL TRANSLATION
INTRODUCTION
CLINICAL TRANSLATION
INTRODUCTION
CLINICAL TRANSLATION
INTRODUCTION
CLINICAL TRANSLATION
INTRODUCTION
CLINICAL TRANSLATION
INTRODUCTION
AIMS▸ Establish penetrance of schizophrenia PRS in real-world
clinical setting
INTRODUCTION
CONSEQUENCES OF INCREASED RISK?
Brainstorm Consortium et al., 2018, Science
INTRODUCTION
CONSEQUENCES OF INCREASED RISK?
Brainstorm Consortium et al., 2018, Science
INTRODUCTION
AIMS▸ Establish penetrance of schizophrenia PRS in real-world
clinical setting
INTRODUCTION
AIMS
▸ Identify pleiotropic effects of genetic risk for schizophrenia
▸ Establish penetrance of schizophrenia PRS in real-world clinical setting
METHODS
CLINICAL VALIDATION
METHODS
CLINICAL VALIDATION
METHODS
CLINICAL VALIDATION
METHODS
CLINICAL VALIDATION
METHODS
CLINICAL VALIDATION91,980 PATIENTS
METHODS
CLINICAL VALIDATION
11,289,707 ICD-9 CODES91,980 PATIENTS
METHODS
CLINICAL VALIDATION
11,289,707 ICD-9 CODES91,980 PATIENTS
MEDIAN EHR LENGTH: 9-13 YEARS
METHODS
CLINICAL VALIDATION
11,289,707 ICD-9 CODES91,980 PATIENTS
MEDIAN EHR LENGTH: 9-13 YEARSMEDIAN # OF VISITS: 50-110
METHODS
GENOTYPES & PHENOTYPES
METHODS
GENOTYPES & PHENOTYPESGE
NOTY
PES
METHODS
GENOTYPES & PHENOTYPESGE
NOTY
PES
METHODS
GENOTYPES & PHENOTYPESGE
NOTY
PES
Low risk High risk
METHODS
GENOTYPES & PHENOTYPES
PHEN
OTYP
ES
GENO
TYPE
S
Low risk High risk
METHODS
GENOTYPES & PHENOTYPES
ICD-9: 295
PHEN
OTYP
ES
GENO
TYPE
S
Low risk High risk
METHODS
GENOTYPES & PHENOTYPES
ICD-9: 295
ICD-9: 298.9
PHEN
OTYP
ES
GENO
TYPE
S
Low risk High risk
METHODS
GENOTYPES & PHENOTYPES
ICD-9: 295
ICD-9: 298.9
ICD-9: 293.81
PHEN
OTYP
ES
GENO
TYPE
S
Low risk High risk
METHODS
GENOTYPES & PHENOTYPES
ICD-9: 295
ICD-9: 298.9
ICD-9: 293.81
Phecode 295
PHEN
OTYP
ES
GENO
TYPE
S
Low risk High risk
METHODS
GENOTYPES & PHENOTYPES
ICD-9: 295
ICD-9: 298.9
ICD-9: 293.81
Phecode 295
PHEN
OTYP
ES
GENO
TYPE
S
Low risk High risk
13,801 ICD-9 codes
METHODS
GENOTYPES & PHENOTYPES
ICD-9: 295
ICD-9: 298.9
ICD-9: 293.81
Phecode 295
PHEN
OTYP
ES
GENO
TYPE
S
Low risk High risk
13,801 ICD-9 codes
1338 phecodes
RESULTS
PENETRANCE
RESULTS
PENETRANCE
0.2
0.4
0.6
0.8
1.0
1.2
1 2 3 4 5 6 7 8 9 10
siteGHS
PHS
VUMC
0.2
0.4
0.6
0.8
1.0
1 2 3 4 5 6 7 8 9 10
Schizophrenia PRS Decile
Cas
e Pr
eval
ence
(%)
RESULTS
OTHER PREDICTORS OF PSYCHOSIS
Cannon et al., 2016, American Journal of Psychiatry
RESULTS
OTHER PREDICTORS OF PSYCHOSIS
Cannon et al., 2016, American Journal of Psychiatry
Conversion to Psychosis
RESULTS
PLEIOTROPY
RESULTS
PLEIOTROPY
Palpitations Dysphagia
Bariatric surgery Obesity
Morbid obesity
Other symptoms/disorders or the urinary system
Dysuria
Schizophrenia and other psychotic disorders Schizophrenia
Mood disorders
Bipolar
Depression
Major depressive disorder
Suicidal ideation or attempt Suicidal ideation
Anxiety, phobic and dissociative disorders Anxiety disorder
Generalized anxiety disorder
Agorophobia, social phobia, and panic disorder
Posttraumatic stress disorder
Personality disorders
Substance addiction and disorders
Alcohol−related disorders
Alcoholism
Tobacco use disorder
Malaise and fatigue
0
5
10
15
20
25
circu
latory
syste
m
cong
enita
l ano
malies
derm
atolog
ic
diges
tive
endo
crine
/meta
bolic
genit
ourin
ary
hemato
poiet
ic
infec
tious
dise
ases
injurie
s & po
isonin
gs
mental
diso
rders
muscu
loske
letal
neop
lasms
neuro
logica
l
pregn
ancy
complic
ation
s
respir
atory
sens
e orga
ns
sympto
ms
Phenotypes
−lo
g 10(p)
RESULTS
PLEIOTROPY
Palpitations Dysphagia
Bariatric surgery Obesity
Morbid obesity
Other symptoms/disorders or the urinary system
Dysuria
Schizophrenia and other psychotic disorders Schizophrenia
Mood disorders
Bipolar
Depression
Major depressive disorder
Suicidal ideation or attempt Suicidal ideation
Anxiety, phobic and dissociative disorders Anxiety disorder
Generalized anxiety disorder
Agorophobia, social phobia, and panic disorder
Posttraumatic stress disorder
Personality disorders
Substance addiction and disorders
Alcohol−related disorders
Alcoholism
Tobacco use disorder
Malaise and fatigue
0
5
10
15
20
25
circu
latory
syste
m
cong
enita
l ano
malies
derm
atolog
ic
diges
tive
endo
crine
/meta
bolic
genit
ourin
ary
hemato
poiet
ic
infec
tious
dise
ases
injurie
s & po
isonin
gs
mental
diso
rders
muscu
loske
letal
neop
lasms
neuro
logica
l
pregn
ancy
complic
ation
s
respir
atory
sens
e orga
ns
sympto
ms
Phenotypes
−lo
g 10(p)
Brainstorm Consortium et al., 2018, Science
CONCLUSIONS
CONCLUSIONS
CONCLUSIONS
CONCLUSIONS▸ Schizophrenia PRS can stratify patients in a real-world
clinical setting
CONCLUSIONS
CONCLUSIONS▸ Schizophrenia PRS can stratify patients in a real-world
clinical setting
▸ We identified many pleiotropic effects of increased genetic risk for schizophrenia
CONCLUSIONS
CONCLUSIONS▸ Schizophrenia PRS can stratify patients in a real-world
clinical setting
▸ We identified many pleiotropic effects of increased genetic risk for schizophrenia
Low risk High risk
CONCLUSIONS
CONCLUSIONS▸ Schizophrenia PRS can stratify patients in a real-world
clinical setting
▸ We identified many pleiotropic effects of increased genetic risk for schizophrenia
Low risk High risk
Low risk High risk
CONCLUSIONS
CONCLUSIONS▸ Schizophrenia PRS can stratify patients in a real-world
clinical setting
▸ We identified many pleiotropic effects of increased genetic risk for schizophrenia
Low risk High risk
Low risk High risk
