Genetics of Depression: Psychotic forms of Unipolar and Bipolar Disorder

J. Raymond DePaulo, Jr., M.D.

Henry Phipps Professor and Director Department of Psychiatry and Behavioral Sciences

Johns Hopkins University School of Medicine

17 Years after the 1st Genomic Map, Why don’t we have the Depression Genes?

• Family Samples, Genome Maps and Linkage Analyses were developed in order to find the genes. What happened?

• Association Studies are being published at a rapid rate. What to make of them?

• What should we do now? – More Genome Scans? Linkage, Association, Expression,

Methylation, Duplication-Deletion, and other scans are possible.– Candidate Gene Studies? Association, Expression, Gene-

Environment Interaction Studies, Genetic Neurobiology, and Protein-Protein Interaction Studies.

– Reduce the Genetic Investment? In the U.S., NIH is short on money while patient-advocacy & legislators want new treatments.

17 Years after the 1st Genomic Map, why don’t we have the Depression Genes?

• 1. What Happened in the Linkage Analyses? Depression and BP are complex. Linkage works best for single gene disorders. Linkage is working here too but slowly & imprecisely.

• 2. What to make of the Association Studies that are being published now? Be skeptical but hopeful. The biotech experts remind us to remember that “90% of positive results will be false positives,” when you are exploring.

• 3. What to do now? Do more genetic studies & others also. The optimal design for genetic studies won’t be known until we find the genes!

American Journal of Psychiatry

161 (April): 595-597, 2004

Editorial

The The

The Genetics of Bipolar Disorder:

Where Do We Stand?

Dairuma Dashi: “Fall down seven times, stand up eight times.”

Thomas Edison: “Hell, there are no rules here. We are trying to accomplish

something.”

Goals of Psychiatric Genetics• Isolate key genes in the brain pathway of

disorders (e.g. Alzheimer’s)

• Genes will:

– Guide the development of diagnostic tests

– Predict treatment responses

– Illuminate environmental risk & protective factors

– Illuminate pathogenesis

– Initiate translational research, i.e., developing new treatments based on basic biology of a disease

8 Consensus Linkage Regions In Bipolar Disorder

4p16

4q35

12q2413q32**

18p11**

18q21-23

22q11-13**

21q22

Chromosomal locations of credible schizophrenia candidate genes:

Adapted from Cloninger CR, PNAS 99(21):13366

32

32

42

31

25

24

23

21

13

21

22

31

35

DISC-1

Ch. 1 Ch. 22

PRODH

COMT

APOL

p

q

RGS4

Am. J. Hum. Genet. 74:1154–1167, 2004

Genomewide Significant Linkage to Recurrent, Early-Onset MajorDepressive Disorder on Chromosome 15q

Peter Holmans, George Zubenko, Raymond Crowe, J. Raymond DePaulo , William Scheftner, Myrna Weissman, Wendy Zubenko, Sandra Boutelle,Kathleen Murphy-Eberenz, Dean MacKinnon, Melvin McInnis, Diana Marta, Philip Adams, James A. Knowles, Madeleine Gladis, Jo Thomas, Jennifer Chellis, Erin Miller, and Douglas LevinsonUniversity of Wales College of Medicine, MRC Biostatistics Unit, United Kingdom; University of Pittsburgh, Pittsburgh; University of Iowa, Johns Hopkins University, Rush University Medical Center, Columbia University, and New York StatePsychiatric Institute and University of Pennsylvania

Genomewide significant linkage observed on 15q25-26, ZLR = 4.14 (equivalent LOD = 3.73) in 297 families with 415 independent affected sib pairs. Needs Replication.

Am. J. Hum. Genet. 76:237–248, 2005

Genomewide Scan for Affective Disorder Susceptibility Loci in Families

of a Northern Swedish Isolated Population

Tine Venken, Stephan Claes, S Sluijs, Andrew Paterson, Cornelia van Duijn, Rolf Adolfsson, Jurgen Del-Favero, Christine Van Broeckhoven

Suggests linkage at 9q31-q34 (MPLOD 3.22) and 6q23-q24 (MPLOD 3.25)

After Linkage tasks are….• Identify Candidate Genes• Find Mutation(s) in the gene (expect > 1 mutation per

gene as in Breast Cancer story)• Assess Frequency of mutation(s) in cases compared to

controls • Prove Pathogenicity: How do pathogenic alleles of gene

cause pathology (and how do protective ones protect)?

This next step could be impossible:•Pathophysiology: How does the pathology lead to development of the psychological features of syndrome?

•How and where in the pathways would you intervene to prevent or cure the disorder?

Region Of Conserved Sequence Around G72/G30 in BP Sample*

G72/G30 Gene Locus, on 13q33, Associated with Bipolar Disorder *Hattori et al, Am J Human Genetics, 2003

P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord.Several P2X receptor subtypes have the unusual property of changingtheir ion selectivity during prolonged exposure to ATP. Brief exposure

to ATP induces the opening of channels that are permeable to bothmono- and divalent cations, whereas more sustained exposures result

in progressive dilatation of the channel pore. The P2X7Rwas originally described in cells of hematopoietic origin, in which itsactivation has been linked to cell lysis, an apparent consequence of

efflux of essential metabolites and intracellular messengers.Although the P2X7R has been found in the nervous system, its functional role in the brain has remained relatively unexplored.

P2X7R is a BP candidate gene on 12q24…based on linkage, association, and functional studies (knockout and

agonist studies) in mice. Barden et al, 2004

Wang et al, Nat Med 10:821, 2004

TPH2 SNP Polymorphisms in Unipolar Disorder

Zill et al, 2004

FKBP5 genotype and Depression

Binder et al, 2004 Nature Genetics

FKBP5

Gluco-Corticoid Receptor

Chaperone

JHU Clinical Study: Psychosis is familial

N=146

N=56

0

5

10

15

20

25

30

35

Percent of affected

1st-degree relatives

with psychotic sxs

p<.003

Relatives of 47psychotic BP Iprobands

Relatives of 18 non-psychotic BP Iprobands

Potash et al., 2001

Do Psychotic Symptoms Cluster in some BP Families?

Sample Size

Odds Ratio- psychosis (psychotic proband vs. not)

P-value

Relatives with any Affective Disorders

400 2.51 .0014

Relatives with BP I 150 3.17 .0039

Potash et al, Am J Psychiatry, 2001; Potash et al, Neuropsychiatric Genetics, 2002

Data from 65 + 69 BP I proband family sets:

Psychotic BP Linkage

Potash et al. 2003

Genetics BP & UP, circa 2005:• Linkage studies of psychiatric disorders are very blunt

instruments but they have guided us to…• Several credible candidate genes for Schizophrenia, based

on location and function, which are now supported and replicated. Candidate mutations exist for 2,COMT & DISC1

• At least one candidate (G72) has been supported and replicated in BP Disorder. Other candidates for BP and UP include P2X7R on 12q (Barden et al, 2004) & XBF.

• Several Schizophrenia and BP/UP related linkages, associations and candidate genes have emerged. Their salience and relationships remain to be explained.

Future Research Directions

• Genome-wide association studies are now feasible (high quality genotypes at $ 0.01 per genotype) and more powerful for complex genetic disorders.

• Phamacogenetics is now possible on a large scale.• Gene-Environment and Gene-Gene studies.• Hypothesis driven studies to determine which phenotype

subtypes are associated with which gene or set of genes.• Studies of the neurobiology of candidate genes and

endophenotypes are proving particularly useful. • These will lead not only to better diagnosis and treatment

predictions but to true understanding of BP and rational approaches to treatment. It will also inform our education of patients, families, and policy makers….stay tuned

Experimental Pathology:

Intranuclear Inclusions in HD Mouse and Human HD

Mouse Model: HD mouse

model labeled Huntingtinantibodies

HD Patient Brainslabeled Huntingtin

Antibodiesand DRPLA w atrophin-1

HD

DRPLA

Merikangas and Risch, Am J Psychiatry, 2003

Clinical Syndrome

Pathological DiseaseEntities

Etiology

BP& UP Disorder: Disease Paradigm

Genes

Brain Pathology

Phenotype

Pathophysiology

Pathogenesis

McHugh & Slavney, 1998; Lewis DA, 1999

Clinical Hypotheses and Bipolar Genes•Anticipation: McInnis et al,1993

–Triplet Repeat Search: Margolis,Swift-Scanlon 2001, 2004

•Parent of origin: McMahon,’95,’97; Stine,’95

–Mitochondrial study: McMahon and Wallace , 2001

–Imprinted Gene Search: Potash and Feinberg

•Co-morbid panic disorder: MacKinnon,’96, ’98

•Rapid Cycling, Rapid Switching: MacKinnon, 2003, 2004

•Episode Frequency: Fisfalen et al, 2004

•BP II: Simpson et al, 1993; McMahon, 2001, Nwulia, 2004

•Psychotic Bipolar Disorder: Potash, 2001, 2002, 2003

BP Meta Analyses: Badner and

Gershon, 2003; Segurado et al, 2003

Relative Risks for Selected psychiatric disorders

• Disorders Relative Risk Heritability

• Bipolar 7-10 60-70%

• Unipolar 2-3 28-40%*

• Schizophrenia 8-10 80- 84%

• Panic Disorder 3-8 50-60%

• Autism 50-100 90%

Merikangas and Risch, Am J Psychiatry, 2003

Paternal haplotype sharing in 18q22 by diagnosis of affected sibling pairs (families # 1-28)

McMahon et al, 2001

Paternal haplotype sharing in 18q22 by diagnosis of affected sibling pairs (in families # 29-58)

McMahon et al, 2001

Schizophrenia-susceptibility genes and synaptic plasticity

Harrison PJ & Owen MJ, 2003

Genes for schizophrenia

Harrison PJ & Owen MJ, 2003

NRG1 = neuregulin-1

DTNBP1 = dysbindin

DAAO = D-aminoacid oxidase

RGS4 = regulator of G-protein signalling-4

PRODH=proline dehydrogenase

COMT=catechol-O-methyltransferase *Some case-control studies negative.

Johns Hopkins Bipolar Genetics Team

• James Potash • Dean MacKinnon • Peter Zandi• Francis Mondimore • Virginia Willour • Haiming Chen• Evaristus Nwulia• Jennifer Payne• Kay Jamison• Susan Folstein • Francis McMahon- NIMH • Melvin McInnis- Michigan • Sylvia Simpson -Colorado

• Barbara Schweizer

• Erin Miller

• Gwen Walker

• Brandi Craighead

• Jenn Coughlin

• Lawrence Lan- Nat Univ Taiwan

• Ann Heinzer

• Yuqing Huo

• Anne Phillips- Vanderbilt

• Jenn Coleman

• Jen Chellis- University of Utah

• Theresa Swift-Scanlan

• Jo Thomas Steel- NIMH

Association of G72/G30 Locus, on 13q33, with Bipolar Disorder Hattori et al, Am J Human Genetics, 2003

Replications now by Chen et al, 2004 and Schumaker et al, 2004

The Alzheimer's Amyloid Pathway

APPSecretase cleavage

InsolubleHard to clearToxic

SolubleEasier to clear

A

BACE1

C- -NCell Lumen

cuts firstBACE1) cuts first

Genetic linkage results for 32 markers on chromosome 18q21-23

McMahon et al, Arch Gen Psychiatry, 2001

TPH2 SNP Polymorphisms in Unipolar Disorder

Zill et al, 2004

Polymorphisms in FKBP5 are associated with increasedrecurrence of depressive episodes and rapid response

to antidepressant treatmentBinder E, Salyakina D, Lichtner P, et al, NATURE GENETICS, 2004

Why so much money and for what?• The Genome Project makes psychiatric genetics

possible or so we think according to skeptics.

• The successes with monogenic disorders (CF) or at least diseases with some monogenic forms (Alzheimer’s) has been good to excellent

• Are we making real progress in BP?

• Gene Identification in Schizophrenia, relevance to Bipolar Disorder

• Clinical Analysis > Clues to Genetic Heterogeneity

• Conclusions, Future Directions, Collaborators

Translational Research

“A translational researcher is someone who takes something from basic research to a patient and measures an endpoint in a patient.”

Source: Lee Nadler, senior V.P. for Experimental Medicine, Dana Farber Cancer Institute, quoted in Nature Medicine, July 2002.