Precision Medicine & Mood Disorders

Mark A. Frye, M.D.

Professor and Chair
Department of Psychiatry & Psychology
Director, Mayo Clinic Depression Center
Precision Medicine: Health Care Tailored For You. Mayo Clinic 17-20 May 2015

Disclosures- Mark A. Frye M.D. 2015

Grant Support
Mayo Foundation , Myriad, National Institute of Alcohol Abuse
and Alcoholism (NIAAA),National Institute of Mental Health
(NIMH), Pfizer

Consultant (Mayo)
Janssen, Mitsubishi Tanabe Pharma Corporation, Myriad,
Sunovion, Teva Pharmaceuticals

Continuing Medical Education (CME)

American Physician Institute
Speakers Bureau
NONE
Financial Interest / Stock ownership / Royalties
NONE
Mayo Clinic
Mayo Clinic has a financial interest in AssureRX and the
technology referenced in this publication/presentation

Bipolar Biobank Outline

Diagnosis & Epidemiology of Bipolar Disorder
Mayo Clinic Bipolar Disorder Biobank
Mission
Community Biobank (control)
Potential Targets
Diagnostic (Pediatric cases in particular)
Antidepressant Induced Mania
Lithium Response
Next Steps

WHO Global Burden of Disease: 1990 DALYs*

World
1.

Lower
respiratoryinfections
2. Diarrheal
diseases
3. Perinatal
conditions
4. Unipolar major
depression
5. Ischemicheart
disease
6. Cerebrovascular
disease
7.

Tuberculosis

8.

Measles

9. Roadtraffic
accidents
10. Congenitalanomalies
20. Alcohol use
22. Bipolar disorder
*DALY = disability-adjusted life year composite measure of time lost due to premature mortality & time lived with disability. Murray and Lopez, 1996.

WHO Global Burden of Disease: 1990 DALYs*

World

Developed Regions

1. Lower respiratory
infections

1.

Ischemic heart disease

2.

2.

Unipolar major depression

3.

Cerebrovascular disease

4.

Road traffic accidents

5.

Alcohol use

6.

Osteoarthritis

Diarrheal diseases

3. Perinatal
conditions
4.

Unipolar major
depression

5. Ischemic heart
disease

7. Trachea, bronchus, &

lung cancers

6. Cerebrovascular
disease

8. Dementia & other

degenerative
& hereditary CNS disorders

7.

Tuberculosis

8.

Measles

9. Road traffic
accidents

9.

Self-inflicted injuries

10. Congenital anomalies

15. Bipolar disorder

10. Congenital anomalies

20. Alcohol use

ALY = disability-adjusted life year composite measure of time lost due to premature mortality & time lived with disability. Murray and Lopez, 1996.

WHO Global Burden of Disease: 1990 DALYs*

Developed Regions

World
1. Lower respiratory
infections

1.

Ischemic heart disease

2.

Diarrheal diseases

2.

Unipolar major depression

3.

Perinatal conditions

3.

Cerebrovascular disease

4.

Unipolar major depression

4.

Road traffic accidents

5.

Ischemic heart disease

5.

Alcohol use

6.

Osteoarthritis

6. Cerebrovascular
disease
7.

Tuberculosis

8.

Measles

9.

Road traffic accidents

10. Congenital anomalies

20. Alcohol use
22. Bipolar disorder

7. Trachea, bronchus, & lung

cancers
8. Dementia & other
degenerative
& hereditary CNS disorders
9.

Self-inflicted injuries

10. Congenital anomalies

15. Bipolar disorder

Developed Regions:
15-44 years old
1. Unipolar major
depression
2.

Alcohol use

3. Road traffic
accidents
4.

Schizophrenia

5. Self-inflicted
injuries
6.

Bipolar disorder

7.

Drug use

8. Obsessivecompulsive disorders
9.

Osteoarthritis

10. Violence

DALY = disability-adjusted life year composite measure of time lost due to premature mortality & time lived with disability. Murray and Lopez, 1996.

Epidemiology Bipolar Disorder

Bipolar I (M / D)

1 % US population

Bipolar II (m / D)
Sex
Onset (average)

1-2% US population
Equal distribution
First impairment (age 15-19)
First treatment (age 20-24)
First hospitalization (age 25)

Recurrence
Average 2.7 - 9 years
Suicide
~35% attempt, ~9% succeed
Predominant phase of illness - depression
Frye et al., 2009; Novick 2010; Bostwick 2003

Bipolar Diagnosis Across the Age Spectrum

Years

Kraepelin, 1921

Time 2002, August 19.

Time 2002, August 19.

Disruptive Mood Dysregulation

Disorder (DMDD)

Time 2002, August 19.

 Established in 2009
Co-PIs: Mark Frye and Joanna Biernacka
DNA matched to a rigorous clinical phenotype to facilitate
genomic and other biomarker studies of:
disease risk
treatment response

Mayo Clinic, Lindner Center of HOPE, U of Minnesota

Currently N>1500 (goal is 4000)

Biobank Enrollment (last 4 weeks)

Data-Locked
(SCID,CQ,PQ,Blood)

Consents
This
week

Total

Mayo

16

832

30

802

Austin

96

LCOH

11

370

U of MN

Clinica
Alemana

Enteredthis
week

Total

Mayo

784

89

Austin

89

18

352

LCOH

348

76

17

59

U of MN

58

Clinica
Alemana

UANL

UANL

Total

27

1374

72

1302

Total

16

1279

Screenfails,
withdrawn

Total

Community Involvement at the National Level

Depression and Bipolar Support Alliance or DBSA (
www.DBSAlliance.org)

Nationwide grass roots organization providing education,

support, and recovery goals through chapter meetings

Willingness to participate survey (i.e. give DNA) in a

genomics biobank listed on DBSA website 2010-2011

385 DBSA members self-reported bipolar diagnosis
Willingness to participate (p, 0.001)
University / Clinic interest (78.2%)
Government (63.4%)
Industry (58.2%)
Frye et al., 2015, in press

Community Involvement at the Local Level

Community advisory board (CAB) initial and annual meeting
to review milestones achieved and problems encountered

9 members (5 males / 4 females, mean age 45.8 years)

Occupations:
attorney
clinical assistant
editor
engineer
physician assistant (ad hoc community IRB member)
2 registered nurses
sales consultant
high school teacher

CAB Recommendations
Diagnosis and treatment selection, particularly in youth /
young adult life, were key recommendations

10-item comprehension questionnaire added a sense of

protection and heightened the informed consent process

Recommendations to consider
an electronic consenting process
educational DVD about the study to potentially engage a
younger audience and to evaluate if this mode of
information delivery was associated with a greater level of
understanding of informed consent

Frye et al., 2015 in press

Frye et al., 2015 Bipolar Disorders in press

2011 MFMER | slide-17

20,000 Community Biobank

20,000 Community Biobank
Janet E. Olson, Ph.D.
Assistant Professor of Epidemiology
Mayo Clinic College of Medicine
JanetE.Olson,Ph.D.
AssociateProfessorofEpidemiology
MayoClinicCollegeofMedicine

The Mayo Clinic Community Biobank

Mayo Clinic Biobank (MCB) was initiated in 2009
Support specific disease-based biobanks by serving as a
source of controls for case-control analyses

Adult participants recruited through

Appointment at Mayo Clinic
Electronic medical records (EMR)
Genotyping data from over 3000 participants available

JE Olson et al., Mayo Clinic Proceedings 2013

The Mayo Clinic Biobank

To access the MCB materials, all proposals are required
to be approved by the MCB Access Committee
Committee members include: general internists,
clinical geneticists, a genetic counselor, a
statistician, a bioethicist, epidemiologists, and basic
scientists, & member of the community advisory
board

As of March 2014
38,000 people have enrolled, provided blood
samples and completed self-report and physician
questionnaires

Mental health questionnaires focused on depression,

mania, drugs of addiction, and anxiety disorders

JE Olson et al., Mayo Clinic Proceedings 2013

Mayo Clinic Bipolar Biobank GOAL # 1

Establish Bipolar Genomic Repository (n= 1,000 BP
patients)
DNA matched to a rigorous clinical phenotype
Future feasibility studies disease risk studies

2011 MFMER | slide-21

heritability

Genetics of Bipolar Disorder

*proportion of the variability in phenotype attributable to additive genetic effects

Ref: J Gelernter. Short Course on the Genetics and Epigenetics of Addiction

Complexity in Identifying Genetic Risk

in Bipolar Disorder
Heritability estimate 80%
Marked heterogeneity & Polygenic
Linkage meta-analyses suggest several susceptibility loci (6q,
8q, 13q, 22q)

Polymorphism in variety of candidate genes

replication difficult
Merged GWAs (3 studies each with 1-2000 cases)
Ankyrin G (ANK3) & CACNA1C
Smith et al., 2009, Sklar et al., 2008, Psychaitric GWAS Consortium 2009

Genetic Studies of Bipolar Disorder (BD)

Genetic risk factors identified to-date explain only a small
proportion of its heritability

Driven by the Psychiatric GWAS Consortium(PGC), most efforts

to discover the missing heritability focus on increasingGWAS
samplesizes

As a complementary approach, we focus on increasing power by

reducing or narrowing the phenotypic (and therefore genetic)
heterogeneity take into account comorbidities

Narrower Phenotypes include

BD and obesity-related disease
BD and addiction
BD and cardiovascular disease
Early onset disease

Percentage

Bipolar Disorder and Obesity

BMI

BD is associated with increasedratesofobesityand

bingeeating(McElroy et al., 2013)

Bipolar Disorder, Obesity and Binge Eating

Association between BD and obesity is wellestablished

Many papers discuss obesity as a consequence

of BD
Preliminary evidence suggesting higher rates of
preexisting obesity
A bi-directional effect has been suggested
More longitudinal research is needed to
investigate causality

Binge eating comorbidity is associated with an

increased psychiatric illness burden
J Affect Disord 2013)

(McElroy et al.,
2011 MFMER | slide-26

Genetic Studies of BMI and Bipolar

Disorder

We used publically available GWAS data

from Genetic Association Information
Network (GAIN) to investigate role of
genetics in BD with comorbid obesity and
binge eating:

Ran GWAS for genetic predictors of BD,

controlling for BMI effects, or testing for /
allowing for BMI-SNP interactions (Winham
et al, Molecular Psychiatry, 2014)

Genetics of BD, taking BMI into account

SNP effects adjusted for

BMI

Main finding in our analysis of GAIN

GWAS data:
SNP-BMI interaction
effects in
rs12772424

Interaction between
TCF7L2 and BMI (p2df = 2.85*10-8)
TCF7L2

SNP effects including

SNP*BMI interaction (2df
test)
Winham et al., 2014,
Molecular Psychiatry

2011 MFMER | slide-28

TCF7L2 (transcription factor 7-like 2)

Regulation of many genes: including amino

acid, lipid and glucose metabolism genes

Part of the Wnt/-catenin canonical pathway,

involved in neurodevelopment, neurogenesis
and neuroplasticity

Prior associations:
Type2diabetes: TCF7L2-BMI interaction
Glucose metabolism
(Obesity, Cancer)
2011 MFMER | slide-29

TCF7L2 (transcription factor 7-like 2)

Associated with psychiatric / neurological

phenotypes:
Psychotic symptoms in human and animal
models

Time 2002, August 19.

Genetics of Early Onset Bipolar Disorder

PrimaryAim:To examine association of earlyonset bipolar disorder with 8 single nucleotide

polymorphisms (SNPs) in 3 genes identified
using GWAS (CACNA1C, ANK3, ODZ4)
TEAMSamplecases
MayoClinicBipolarDisorderBiobank
cases
Early Onset Cases (<19)
Late Onset Cases
MayoClinicBiobankcontrols

Slides courtesy of Dr. Paul Croarkin

Candidate SNPs and Their Effects On Bipolar Disorder

MAF1

MAF2

ORMA2

Reference

A/G

0.18

1.18

PGC-BD, Nat Genet, (2011)

rs9804190

C/T

0.236

0.21

0.86

PGC-BD, Nat Genet, (2011)

rs1099433

C/T

0.063

0.06

1.35

Ferreira, Nat Genet, (2008)

rs1938526

A/G

0.075

0.06

1.32

Ferreira, Nat Genet, (2008)

CACNA1C rs1084863

C/T

0.385

0.40

1.08

Green, Mol Psych, (2013)?

G/A

0.385

0.34

1.11

Ferreira, Nat Genet, (2008)

rs10245823 G/A

0.397

0.37

1.11

Ferreira, Nat Genet, (2008)

rs4765913

0.276

0.21

1.15

PGC-BD, Nat Genet, (2011)

Gene

SNP

Major/minor
allele

ODZ4

rs1257677
5

ANK3

2
rs1006737

T/A

MAF from 1000 genomes CEU sample

MAF from prior BP studies
2
ORMA = minor allele odds ratio, based on PGC analysis (PGC-BD, Nat Genet, (2011))
3
rs1024582 was excluded from risk score calculation due to high LD with other SNPs
1
2

rsreferencesequencenumber(NationalCenterforBiotechnologyandInformation)

Clinically Significant Variations

Gene

Result

Relevance

SLC6A4

L/S

Possible poor response or

adverse events with SSRIs

5HT2C

C/C

Associated with increased

weight gain with atypical
antipsychotics

CACNA1C

G/A

Altered function of brain

calcium channels, changes
in neuronal excitability,
clinical mood lability

MTHFR

C/T

Reduced conversion to
methyl folate

CYP2D6

*2/*4

Intermediate metabolizer

CYP2C19

*1/*17

Ultrarapid metabolizer
Slides courtesy of Dr. Paul Croarkin
2011 MFMER | slide-34

Clinically Significant Variations

Gene

Result

Relevance

DRD2

NS/NS

No clinical significance

ANK3

C/C

No clinical significance
(ankyrin proteins-role in
sodium channel function)

COMT

Val/Met

No clinical signficance
Val variant catabolizes
dopamine 4x greater rate

CYP3A4/5

*3/*3

Poor metabolizer

2011 MFMER | slide-35

Mayo Clinic Bipolar Biobank GOAL # 2

Establish Bipolar Genomic Repository (n= 1,000 BP
patients)
DNA matched to a rigorous clinical phenotype
Pharmacogenomic Probe stduies
Lithium response
Antidepressant Induced Mania
Future feasibility studies disease risk studies

2011 MFMER | slide-36

Pharmacogenomics

Study of genetic variation and its effect on variation

in psychotropic drug response

Research implications
Pathophysiology of complex genetic, multifactorial
illnesses
Development of new medications that are more
efficacious, better tolerated, more personalized

Clinical uses
Prediction of dose, adverse effects, therapeutic
response

Lithium Response in Bipolar Disorder

Historical Gold Standard
Distinct clinical features define
response phenotype

Clinical predictors account for < 50%

of variance suggesting genetic
factors

Prophylactic response has been

reported to be familial

Growing body of drug mechanism of

action (MOA) will enhance search for

candidate genes

Frye et al., 1998, Serretti et al., 2005, Grof

2002, Alda et al. ,2005

http://www.coligen.org/images/clg-logo-gruen.gif
NationalInstituteofMentalHealth(NIMH)

InternationalGroupforTheStudyofLithium
TreatedPatients(IGSLI)
2011 MFMER | slide-39

Frye, NEJM 2011;364(1):51-59

Risk Factors for Switch

MixedDepression
Tricyclic antidepressant (TCA) use
History of antidepressant-induced mania (AIM)
Absence of Antimanic Mood Stabilizer
Low thyroid stimulating hormone (with TCAs)
Polymorphism(s/sors/l)at5-HTTLPR
Hyperthymic temperament
Comorbid alcoholism
Female gender and comorbid anxiety disorder
Age (peripubertal > adolescents)
BP I > BP II
Frye et al., 2009 Am J Psychiatry

Mayo Clinic Individualized Medicine Biobank

for Bipolar Disorder (BP)
SLC6A4 polymorphism & Antidepressant Induced Mania

2011 MFMER | slide-42

Mayo Biobank Study:

Antidepressant Induced Mania (AIM +) Phenotype

Mania (hypo) within 60 days of starting antidepressant

treatment or changing dose

Secondary factors controlled in analysis

Antidepressant class
Concomitant mood stabilizer
Bipolar I vs II
Rapid cycling at the time of AIM/AIHM
Ethnicity
Age
Frye et al., 2015 J Clin Psychiatry
2011 MFMER | slide-43

SLC6A4 and AIM: Mayo Pilot Study

295 White non-Hispanic subjects
113 AIM+ cases, 182 AIM- controls
Genotyped for:
5HTTLPR (long/short alleles; L/S)
rs25531 SNP in the promoter (A/G)
Intron 2 VNTR (9, 10, 12 repeats)
Analysis:
Logistic regression to test for association of genetic

variants with AIM; Adjusted for age

Haplotype analysis

SLC6A4 S Allele and AIM: Meta-Analysis Results

StudyCasesControls
(N)(N)
Mundo2729
Rousseva83149
Serretti150230

Masoliver3766
Ferreira4369
Mayo113182

OR = 1.35 (95% CI: 0.99-1.85)

P = 0.059

Summary

OR

Meta-analysis marginally significant evidence of association between S allele and AIM+ (p=0.059)

Frye et al 2015 J Clin Psychiatry

Pharmacogenomic Haplotype Analysis

L-A-10 Protective
Haplotype

Freq.

Score

Simp

Maxstat
simp

Global
simp

L-A-10

0.344

-2.448

0.012

0.047

0.020

L-G-12

0.027

-1.555

0.14

--

S-A-10

0.214

0.144

0.86

--

L-A-12

0.136

0.965

0.31

--

S-A-12

0.225

1.034

0.28

--

Cases N= 113; Controls N= 182

Haplotype analysis suggests an association between AIM and haplotypes composed of

the 5HTTLPR, rs25531, and the intron 2 VNTR in the SLC6A4 gene, with the L-A-10
haplotype being associated with reduced risk of AIM
Frye et al., J Clin Psychiatry 2015

PharmacogenomicTargetsinBipolarDisorder

Bipolar Disorder -Multiple risk genes

GWAs and candidate genes have merit
Individualized Treatment response
faster mood stabilization
fewer unsuccessful treatment trials
Primary prevention of adverse events
genomic predictors of response
primary prevention (i.e. AIM +, SJS/ TEN, TD)
gene x environment have only begun to be explored
stressors, comorbidity, duration of illness
Rigorous Phenotype assessment beyond DSM V / ICD 11
2011 MFMER | slide-48

MayoClinic

SupportedbytheMarriottFoundation

Mark A. Frye M.D. Co-PI

UniversityofMinnesota
Scott J. Crow, M.D.

Joanna M. Biernacka Ph.D. Co-PI

David J. Bond M.D., Ph.D.

Jarrod Leffler Ph.D

LindnerCenterofHOPE

Simon Kung, M.D.

Susan L. McElroy, M.D.

Paul Croarkin D.O.
Brian Palmer M.D.

Leah Casuto, M.D.

Miguel Prieto M.D.

Marin Veldic M.D.

Stacey Winham Ph.D.
William V Bobo M.D.
Alfredo Cuellar Barboza M.D.

AdvisorBoard
RobertM.Post,M.D.
George Washington University

PediatricKeyOpinionLeaders
GabrielleA.Carlson,M.D.
Stony Brook

MelissaDelBello,M.D.
University of Cincinnati

KikiChang,M.D.
Stanford School of Medicine

CathrynGalanter,M.D.
SUNY Downstate

StevenHirschM.D.
Bethesda

VictoriaCosgrovePhD.
Stanford School of Medicine

PeterJensen,MD
REACH Institute

FlavioKapczinskiM.D.
UT Houston

KathrynR.Cullen,M.D.
University of Minnesota

KarenDineen-Wagner,M.D.,
PhD.
The University of Texas Medical
Branch
Steering Committee Co-Chair

AnneDuffy,M.D.;FRCPC
University of Calgary
GianricoFarrugiaM.D
Mayo Clinic

PaulE.KeckJr.M.D.
Lindner Center of Hope
MartinSchallingM.D.
Karolinska Institutet
PamelaSklarM.D.,Ph.D.
Mount Sinai Hospital
AnaAndreazza,PhD
University of Toronto

BonnieKlimesDougan,PhD.
University of Minnesota

EricYoungstrom,M.D.
University of North Carolina at
Chapel Hill

MayoClinicDepressionCenter
Mark A. Frye M.D. Director

MarkA.FryeM.D.MarinVeldic,M.D.WilliamBobo,M.D.KatherineMooreM.D.

SimonKungM.D.BrianPalmerM.D.PaulCroarkin,D.O.JarrodLefflerPh.D.

OsamaAbulseoudM.D.Doo-SupChoiPh.D.JoannaBiernackaPh.D.SusannahTyePh.D.

MayoClinicDepressionCenter

Funding for this work was provided by the Marriott Foundation

Thank you to the bipolar patients and their families who have
contributed to the development and richness of this clinical
resource
2011 MFMER | slide-53

2011 MFMER | slide-54