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 
respiratory infections
2. Diarrheal 
diseases
3. Perinatal 
conditions
4. Unipolar major
depression
5. Ischemic heart 
disease
6. Cerebrovascular 
disease
7.

Tuberculosis

8.

Measles

9. Road traffic 
accidents
10. Congenital anomalies
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

0

96

7

LCOH

11

370

U of MN

0

Clinica
Alemana

Entered this 
week

Total

Mayo

8

784

89

Austin

0

89

18

352

LCOH

8

348

76

17

59

U of MN

0

58

0

0

0

0

Clinica
Alemana

0

0

UANL

0

0

0

0

UANL

0

0

Total

27

1374

72

1302

Total

16

1279

Screen fails,
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
Janet E. Olson, Ph.D.
Associate Professor of Epidemiology
Mayo Clinic College of Medicine

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 GWA’s (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 increasing GWAS 
sample sizes

• 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 increased rates of obesity and 
binge eating (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/β-catenin canonical pathway,
involved in neurodevelopment, neurogenesis
and neuroplasticity

• Prior associations:
• Type 2 diabetes: 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

• Primary Aim: To examine association of earlyonset bipolar disorder with 8 single nucleotide
polymorphisms (SNPs) in 3 genes identified
using GWAS (CACNA1C, ANK3, ODZ4)
• TEAM Sample cases
• Mayo Clinic Bipolar Disorder Biobank 
cases
• Early Onset Cases (<19)
• Late Onset Cases
• Mayo Clinic Biobank controls

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

6

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

rs reference sequence number (National Center for Biotechnology and Information)

“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
  National Institute of Mental Health (NIMH) 

International Group for The Study of Lithium 
Treated Patients (IGSLI)
©2011 MFMER | slide-39

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

Risk Factors for Switch
• Mixed Depression
• Tricyclic antidepressant (TCA) use
• History of antidepressant-induced mania (AIM)
• Absence of Antimanic Mood Stabilizer
• Low thyroid stimulating hormone (with TCAs)
• Polymorphism (s/s or s/l)  at 5-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
Study      Cases  Controls
                   (N)     (N)
Mundo        27      29
Rousseva   83      149
Serretti       150     230  
   
Masoliver    37      66
Ferreira       43      69      
Mayo          113    182

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

Sim p

Max stat 
sim p

Global 
sim p

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

Pharmacogenomic Targets in  Bipolar Disorder

• 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

Mayo Clinic

Supported by the Marriott Foundation

Mark A. Frye M.D. Co-PI

University of Minnesota 
Scott J. Crow, M.D.

Joanna M. Biernacka Ph.D. Co-PI

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

Jarrod Leffler Ph.D
Lindner Center of HOPE 

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.

 Advisor Board
Robert M. Post, M.D. 
George Washington University

Pediatric Key Opinion Leaders
Gabrielle A. Carlson, M.D.  
Stony Brook

Melissa DelBello, M.D.
University of Cincinnati

Kiki Chang, M.D.
Stanford School of Medicine

Cathryn Galanter, M.D.
SUNY Downstate

Steven Hirsch M.D.
Bethesda

Victoria Cosgrove PhD.
Stanford School of Medicine

Peter Jensen, MD
REACH Institute

Flavio Kapczinski M.D.
UT Houston

Kathryn R. Cullen, M.D.
University of Minnesota

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

Anne Duffy, M.D.; FRCPC
University of Calgary
Gianrico Farrugia M.D
Mayo Clinic

Paul E. Keck Jr. M.D.
Lindner Center of Hope
Martin Schalling M.D.
Karolinska Institutet
Pamela Sklar M.D., Ph.D.
Mount Sinai Hospital
Ana Andreazza, PhD
University of Toronto

Bonnie Klimes Dougan, PhD.
University of Minnesota

Eric Youngstrom, M.D.
University of North Carolina at
Chapel Hill

Mayo Clinic Depression Center
Mark A. Frye M.D. Director

     Mark A. Frye M.D.            Marin Veldic, M.D.              William Bobo, M.D.       Katherine Moore M.D. 

      Simon Kung M.D.             Brian Palmer M.D.            Paul Croarkin, D.O.         Jarrod Leffler Ph.D. 

Osama Abulseoud M.D.     Doo-Sup Choi Ph.D.       Joanna Biernacka Ph.D.      Susannah Tye Ph.D. 

Mayo Clinic Depression Center

 
 

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

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