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The Genetics PTSD:
New findings from the Psychiatric Genomics Consortium
Karestan C. Koenen, [email protected]
X
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Why study the genetics of PTSD?
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Yehuda, R. et al. (2015) Post-traumatic stress disorder. Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.57
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The idea that constitutional factors – those within the individual – influence response to trauma is not new.
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“There was evidence that the terrifying stresses of war tended to provoke anxiety states to a significantly preferential extent, but they did so far from regularly. A more important determinant of the type of response was the constitution of the individual, as shown by his family history, previous life, and personality.”
Eliot Slater, 1944
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PTSD is heritable.
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Twin studies rely on a natural experiment to assess heritability
Monozygotic twins:
share 100% of their genes
Dizygotic twins:
share 50% of their genes
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PTSD heritability from twin studies is similar to other psychiatric disorders
Sullivan, Daly, and O'Donovan. Nature Reviews Genetics. 2012
PTSD: Males
PTSD: Females
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Genetics provides foundational insights into biology that may eventually impact clinical care.
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0
3
6
9
12
15
Number of
Mech.
Distinct
Drugs
1950's Present
Depression Schizophrenia Heart Disease
Identifytarget
Chemicalscreening
Clinical trials
Most therapies developed through traditional approaches fail to have efficacy
Animal models
No novel therapies for neuropsych disorders
Finding the genes and mutations that cause disease is the most reliable means of gaining the insights required
PTSD psychopharmacology: Progress needed
• The only FDA approved drugs for PTSD are the SSRIs: sertraline (Zoloft) and paroxetine (Paxil).
• Overall response rate estimated at about 60% with only 20-30% achieving complete remission
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So how do we find genes for PTSD?
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If we knew what the genes were, they’d be easy to find…
▪ 1991-2015 – the era of the candidate gene association study in PTSD
▪ Hallmarks: poor statistical practice, optimistic data interpretation, few if any reproducible results
▪ Outcome: little durable knowledge
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Initial attempts to identify genes were not successful for complex diseases broadly . . .
Dark Ages of complex trait genetics
Science 2002. Glazier, Nadeau & Aitman. Finding Genes that Underlie Complex Traits.
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Progress required an intellectual shift from Mendelian to complex trait genetics
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Complex trait genetics
▪ Instead of one gene determining a disease or trait, many genes each exert a small influence
▪ None by themselves can “cause” or “explain” the disease or trait fully – but together with environmental influences combine to define an individual outcome
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Progress also required many fundamental paradigm shifts
▪ Understanding the genome and the fundamental nature of human variation
▪ Dramatic technological advances in our ability to access genomes
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A genomic approach: Compare variation in entire genome in many thousands of genomes
People with and without disease
Define the genetic basis of the disease
Humangenome
Normal
Humangenome
Tumor
Define the genetic basis of cancer
Cells with and without cancer
Microbialgenome
Resistant
Sensitive
Define the genetic basis of virulence
Microbes that do and do not kill
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Consortium approach needed
PGC
Psychiatric Genomics Consortium
(and 800+ others)
Patrick Sullivan Mark Daly
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Sample size accelerates discovery
2009: 2601 cases → 0 hits
2011: 9394 cases → 5 hits
2012: 25K cases → 62 hits
2014: 36K cases → 108 hits
Numbers presented represent samples of European Ancestry
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60995 cases, 102860 controls
155 genome wide significant sites
Courtesy of Stephan Ripke
Sample size accelerates discovery (2016)
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Initial molecular parts list for schizophrenia
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Can the PGC provide a road map for PTSD?
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PGC PTSD Working Group founded
Kerry Ressler Israel LiberzonKarestan Koenen Caroline Nievergelt
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PGC PTSD: Data freeze I
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Lead Analyst Laramie Duncan, PhD
PGC PTSD: Data freeze I
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Adapted from Gratten et al. 2014
Trajectories of GWAS discoveries
Freeze 1EA
~2.4k
Freeze 1trans-ethnic
>5k
Goal: reach inflection point
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PGC PTSD: Data freeze 2
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GWAS analysis strategy needs to account for diverse ancestries
EUA meta-analysisN = 174,659
23,212 cases (13.3%)
AFA meta-analysisN = 15,339
4,363 cases (28.4%)
Meta-analysis across ancestry groups
N = 195,701 29,556 cases (15.1%)
AMAN = 5,703 1,981 cases
(34.7%)
Freeze 1
CVB RFA
GWAS summary data
Dataset Type51 European Ancestry (EUA) 30 African Ancestry (AFA) 6 Latino (AMA)
MRSC FEENSAFR DCSRDNHS TEICGSDC NIUFSCD WACH
COGB EGHSNSS1 ADNHNSS2 COM1PPDS GRACSTRO YEHU
GTPC* BAKEKSUD VRISBOBA WANGKMCT MIREPORT NCPT
MRSC FEEN
ONGA DCSR
NHS2 TEIC
GSDC NIUT
FSCD NCMH
COGA EACR
COGB WACH
BRYA BETR
SATU SEEP
DEFE COM1
NHRV FTCB
NSS1 GRAC
NSS2 YEHU
PPDS BAKESTRO VRIS
GTPC* WANGGMFR VETSAKSUD PRISBOBA INTRKMCT DAMIPORT DAIPGUTS QIMRNHSY MIRERING NCPT
BRY2 TRAC
UKBB
MRSC
NSS1
NSS2
PPDS
STRO
PROM
Studies analyzed together
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Three major findings:
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1. PTSD is heritable.
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PTSD is heritable
PTSD PTSD.F PTSD.M SCZ BIP MDD
LD
SC
He
rita
bili
ty
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
Tw
in S
tud
y H
erita
bili
ty
PGC-PTSD
Published data used for LDSC (SCZ, BIP, MDD)Heritability (h2) Proportion of phenotypic variation accounted for by genetic variation.
SNP-chip heritability (h2SNP) Proportion of
phenotypic variation accounted for by measured genetic variation.
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Sullivan et al. 2017
SNP heritability is lower than twin heritability
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Nievergelt et al. in prep.
Group Sample NCases NControls h2snp 95%CI z p-value
All PGC2 23,212 151,447 0.05 0.03-0.07 5.53 3.18E-08PGC1.5 12,823 35,648 0.05 0.01-0.08 2.54 0.011
UKBB 10,389 115,799 0.17 0.14-0.21 8.75 2.06E-18Men PGC2 9,908 75,605 0.01 -0.03-0.05 0.49 0.63
PGC1.5 6,364 23,905 0.01 -0.05-0.07 0.39 0.69UKBB 3,544 51,700 0.15 0.05-0.24 2.99 0.0014
Women PGC2 12,973 73,627 0.10 0.07-0.13 6.50 8.03E-11PGC1.5 6,128 9,528 0.21 0.11-0.31 4.20 2.66E-05
UKBB 6,845 64,099 0.19 0.13-0.25 6.36 2.00E-10
• Considerable range in SNP heritability • SNP heritability women > men but not in UK Biobank• Similar findings in subjects of African ancestry (using GCTA)• SNP heritability of major depression 8.7% (Wray, 2018, Nature Genetics)
PTSD is heritable, in the range found for major depression
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2. PTSD shares genetic risk with other psychiatric disorders, as well as other traits.
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Polygenic risk score (PRS)
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Genetic risk for PTSD is correlated with that for other mental disorders and traits
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A) PTSD B) MDD C) SCZ D) BPD E) ADHD
−1.0 −0.5 0.0 0.5 1.0 −1.0 −0.5 0.0 0.5 1.0 −1.0 −0.5 0.0 0.5 1.0 −1.0 −0.5 0.0 0.5 1.0 −1.0 −0.5 0.0 0.5 1.0
Coronary artery diseaseRheumatoid Arthritis
AsthmaYears of schooling 2016Years of schooling 2013
College completionChildhood IQ
Parents age at deathMothers age at deathFathers age at death
Number of children ever bornAge of first bir th
Age at MenopauseAge at Menarche
Squamous cell lung cancerFormer vs Current smoker
Ever vs never smokedCigarettes smoked per day
Waist−to−hip ratioWaist circumference
Type 2 DiabetesTriglycerides
Hip circumferenceHDL cholesterol
Childhood obesityBody mass index
Body fatTiredness
Subjective well beingSchizophrenia
PGC cross−disorder analysisNeuroticism
Major depressive disorderInsomnia
Depressive symptomsDaytime sleepiness
Bipolar disorderAutism spectrum disorder
Anxiety disordersAnorexia Nervosa
ADHD
Genetic Correlation (rg)
Tra
it
Category●
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Psychiatric
Anthropometric
Smoking Behaviour
Reproductive
Aging
Education
Autoimmune
Cardiometabolic
Nievergelt et al. in prep.
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Nievergelt et al. in prep.
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3. PTSD remains underpowered, but the first probable hits are beginning to emerge.
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Adapted from Gratten et al. 2014
Trajectories of GWAS discoveries
Freeze 1EA
~2.4k
Freeze 2European
>23.2k
Freeze 1trans-ethnic
>5k
Goal: reach inflection point
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Summary of Freeze 2 Results
Courtesy of Caroline Nievergelt
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Courtesy of Caroline Nievergelt
Summary of Freeze 2 Results
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At least three challenges need to be addressed in moving forward . . .
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1. PTSD is still underpowered: Continue to increase sample size
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2. PTSD is conditional on trauma and heterogeneous: Refine trauma and PTSD phenotypes
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Trauma exposure is heritable
0
10
20
30
40
50
60
AssaultiveViolence
Served inSoutheast Asia
CombatExposure
Awarded aCombat Medal
Heritability for specific types of traumatic events
%
Stein et al. (2002) American Journal of Psychiatry Lyons et al. (1995) American Journal of Medical Genetics
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Heritability of childhood trauma
Courtesy of Shareefa Dalvie
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PTSD is heterogeneousP
TSD d
iagno
sis: Crit. A
plu
s1
B, 1
C, 1
C, 2
D, 2
E symp
tom
s
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N=146,660 European-American Courtesy of Joel Gelernter, In Press, Nature Neuroscience
Results from the Million Veterans Program CSP575b: GWAS of Reexperiencing in European Americans
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3. GWAS hits are not an end in themselves: Translation needed to improve patients’ lives
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Psyc– serendipity (!)
Genetic findings
Biology
Pathways / “read outs”
Rational drug discovery
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Genetic findings inform follow-up studies.
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1200
1300
1400
1500
1600
1700
1800
T carriers CC allele
Amygdala Volume
Vo
lum
e in
mic
rolit
ers
rs115539978 SNP
0
5
10
15
20
25
30
35
40
45
T carriers CC allele
Habituation of Startle
Dif
fere
nce
in S
tart
le (
uS)
rs115539978 SNP
Functional imaging and psychophysiology in the Grady Trauma Project
Torsten Klengel
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PCG PTSD Working Group
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Therapeutics
Pathophysiology
Disease associated genes
Genetics
From the population to clinical medicine
Diagnostics
Goal: to provide durable insights into disease biology that ultimately impact clinical care
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PGC PTSD Working Group Funding
Magali Haas (Cohen Veterans
Bioscience)
Caroline Nievergelt (Contact PI, NIMH grant)
Steve Hyman (Stanley Center)
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Acknowledgments: MVP Results
CSP#575B
M. Aslan J. Gelernter S. Pyarajan
D. Beck K. Harrington R. Quaden
Z. Cheng J. Honerlaw K. Radhakrishnan
Q. Chen G. Huang F. Sayward
K.H. Cheung J. Ko D. Levey
K. Cho W. Lance M. Stein
S. Cissell Y. Li N. Sun
J. Concato S. Muralidhar N. Usher
P. Crutchfield Y. Nunez S. Whitbourne
J. Deen T. O’Leary H. Zhao
J.M. Gaziano R. Pietrzak R. Polimanti
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Acknowledgements: PGC PTSD Freeze 2
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Welcome users of VHA TRAIN!
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SAVE THE DATE: Third Wednesday of the Month from 2-3PM (ET)
UPCOMING TOPICS
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August 21 Focal Brain Stimulation for PTSD Paul Holtzheimer, MD
September 18 Treating PTSD and Cognitive Impairment from
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Amy Jak, PhD
October 16 Unconventional Interventions for PTSD: State of the
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Paul Holtzheimer, MD
November 20 Addressing Sleep: A Strategy for Symptom Reduction
& Suicide Prevention?
Wilfred Pigeon, PhD
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Presentations of PTSD
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