Psynomics, Inc.◦ Offers genetic testing in psychiatry

Symptoms of mood:◦ Low mood, sadness, or sometimes irritability◦ Loss of interest and pleasure◦ Hopelessness◦ Suicidality

Cognitive symptoms:◦ Problems with memory & concentration (often most

prominent symptom in older people)◦ Indecisiveness◦ Low self esteem, worthless, guilt

Somatic symptoms:◦ Low energy◦ Insomnia, hypersomnia, early morning awakening◦ Loss of appetite, weight loss or increased appetite and

wt. gain

DSM4 Criteria◦ 5 of 9 criteria◦ Two week duration◦ Clinically significant distress or impairment

Other Associated Symptoms◦ Decreased libido◦ Anxiety or panic attacks◦ Somatization◦ Psychosis

Mood congruent◦ “Pseudo-dementia”◦ Alcohol and substance abuse

DSM4 Criteria◦ One week duration◦ Elevated or irritable mood◦ Inflated self esteem or grandiosity◦ Decreased need for sleep◦ Increased or pressured speech◦ Flight of ideas or racing thoughts◦ Distractibility◦ Increased goal directed activity◦ Risky pleasures◦ Functional impairment

Severity◦ Mania – Bipolar I◦ Hypomania

No functional impairment Bipolar II

Other Associated Symptoms◦ Increased libido◦ Spending sprees◦ Psychosis◦ Antisocial behavior◦ Alcohol and substance abuse◦ Suicidality

Age of onset early twenties 1-2% prevalence Unipolar depression is about 5 times

more common Male and Female prevalence equal 60-80% of cases begin with mania 4-18% of those with depression later

have mania Stable features

◦ Seasonality (Seasonal Affective Disorder)◦ Psychosis◦ Rapid cycling

Related syndromes and disorders◦ Mixed states◦ Schizoaffective disorder◦ Substance abuse and alcoholism

Affective Illness In First Degree RelativesAffective Illness In First Degree Relatives

Bipolar Probands Relatives Morbid Risk (%)

at Risk BP UP

Perris, 1966 627 10.2 0.5Winokur and Clayton, 1967 167 10.2 20.4Mendlewicz and Rainer, 1974 606 17.7 22.4Goetzl et al., 1974 212 2.8 13.7Helzer and Winokur, 1974 151 4.6 10.6Gershon et al., 1975 341 3.8 6.8James and Chapman, 1975 239 6.4 13.2Johnson and Leeman, 1977 126 15.5 19.8Petterson, 1977 472 3.6 7.2Smeraldi et al., 1977 172 5.8 7.1Trzeblatowska-Trzeciak 11.4 0.0Angst, 1980 400 2.5 7.0Dunner, Go, and Fieve, 1980 1199 4.2 8.2Taylor, Abrams, and Hayman, 1980 600 4.8 4.2Gershon et al., 1982 598 8.0 14.9Tsuang et al., 1985 608 3.9 9.1Rice et al., 1987 557 5.7 23.0Total 7364 6.8 10.4

Twin Studies of Affective IllnessTwin Studies of Affective Illness

Study Monozygotic Dizygotic Concordance (%) Concordance (%)

Luxenberger, 1930 3/4 75.0 0/13 0.0Rosanoff et al., 1935 16/23 69.6 11/67 16.4Slater, 1953 4/7 57.1 4/17 23.5Kallman, 1954 25/27 92.6 13/55 23.6Harvald and Hauge, 1965 10/15 66.7 2/40 5.0Allen et al., 1974 5/15 33.3 0/34 0.0Bertelsen, 1979 32/55 58.3 9/52 17.3

TOTAL 95/146 65.0 39/278 14.0

Spectrum disorders are partially genetically distinctSpectrum disorders are partially genetically distinct

Twins are partially concordant for polarity

Concordance in Monozygotic Pairs

Polarity

BP-BP 14UP-UP 11BP-UP 7

32

25/32 (78%) of monozygotic pairs were specific for polarity.

Bertelsen, 1979

Bipolar II has been observed to occur more often in the families of bipolar II probands than bipolar I probands

A subset of genes may be specific for bipolar II

Probands Relatives (%)Bipolar I Bipolar II Non-bipolar

Bipolar I 8.5 6.1 61Bipolar II 3.0 30.3 63.6Non-bipolar 1.9 6.6 59

Coryell et al, 1984

Forms that cluster together in the same families◦Psychotic mania (Potash)◦Bipolar disorder with panic attacks

(MacKinnon)◦Suicidality (MacKinnon)

Tsuang 1980

*** **

*

Significantly different from control rate*

Proband Co-twin MZconcordance(%)

DZ concordance(%)

MZcorrelation

DZcorrelation

Schizophrenic Schizophrenic 40.8 5.3 0.83 0.31

Manic Manic 36.4 7.4 0.83 0.46

Schizoaffective Schizoaffective 39.1 4.5 0.85 0.37

Schizophrenic Manic 8.2 0.0

Manic Schizophrenic 13.6 3.7 0.51 0.12

Schizophrenic Schizoaffective 8.2 5.3

Schizoaffective Schizophrenic 26.1 4.5 0.60 0.37

Schizoaffective Manic 26.1 0.0

Manic Schizoaffective 31.8 3.7 0.78 0.24

Cardno 2002

Family members have a 7 fold increased risk for illness

Only about 65% of what causes bipolar disorder is inherited (reduced penetrance)

Milder forms of the phenotype are frequently found in relatives of bipolar probands

Some aspects of the spectrum are more like quanitatitve traits

While other bipolar spectrum traits are in part genetically distinct.

The bipolar spectrum overlaps with other psychiatric diagnoses

Single Major Locus◦One gene of large effect transmits the trait◦Mendelian patterns of transmission◦Heterogeneity - different genes in different

families Polygenic or Multifactorial Transmission◦Many genes each contribute a small effect◦Quantitative traits◦Additive◦Epistatic

Mixed Model

B

B B

A

AA

•One gene explains most of the genetic variance in a single family•Different genes in different families

More Psychosis Genes

Pop

ulat

ion

Fre

quen

cy

Major depression

Bipolar II

Bipolar I

Schizoaffective Disorder

Affective Temperaments

Schizophrenia

More Bipolar Genes

Pop

ulat

ion

Fre

quen

cy

Bipolar DisorderHyperthymia

Less fit

More fit

Primary genetictransmission

Unipolar

Bipolar 3

Bipolar 1

Bipolar 2

Gene A

Gene B

Gene C

Gene D Gene E

Spectrumtemperaments

Allelic Heterogeneity

Gene A

X

XMutation B

Mutation S

Schizophrenia

Bipolar Disorder

Non-specific gene+ Gene B

+ Gene S Schizophrenia

Bipolar Disorder

Gene-gene interactions

Non-specific gene+ Environment B

+ Environment S Schizophrenia

Bipolar Disorder

Gene-environmental interactions

All of the above

Sequence◦ Sequenced all 3 billion base pairs in the human

genome◦ Only ~18,000 human genes

HapMap Project◦ Identified over 8M SNPs◦ 4 populations◦ SNPs occur in haplotype blocks◦ Tools for Genome-wide association

Step Methods ResolutionLinkage Microsatellite markers 5-20 Mb

Association Single Nucleotide Polymorphisms (SNP) 5-25kb

Positional candidates Database

Mutation screening Sequencing 1 bp

Functional testing Cellular and animal models

Success when a variant is found that 1. affects function of the gene2. is associated with illness

Hu

man

Gen

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e P

roje

ct

0

1

2

3

4

960 1160 1360 1560

5 6 7 8

0

1

2

3

4

0 100 200 300 400 500 600 700 800 900 1000

1 2 3 4

0

1

2

3

4

1700 1900 2100 2300 2500

14131211109

0

1

2

3

4

2550 2750 2950 3150 3350

15 17 19 21 22201816

Genome Survey of 20 Bipolar FamiliesM

axi

mu

m L

OD

Sco

re

Genetic Distance (cM)

LocusD22S420D22S264D22S427D22S425D22S539D22S303D22S257

D22S1174D22S315

D22S1164D22S926D22S925D22S421D22S419D22S429

D22S1144D22S689D22S684D22S693D22S691D22S1juD22S5ju

D22S277D22S683D22S278

D22S1142D22S283D22S692

D22S1045D22S445D22S307D22S270ata5f505D22S274

Chromosome 22Summary of results in Bipolar Disorder and Schizophrenia

13

11.2

11.1

11.22

12.1

12.3

13.2

13.32

UCSD genome scan, LOD 2.2

Detera-Wadleigh et al., NIMH intramural, LOD 2.5

NIMH GIBP consortium, LOD 2.5

Myles Worsley et al., LOD 3.5

GRK3

Bipolar DisorderSchizophrenia

Pulver et al., LOD 2.8

UCSD genome scan, LOD 3.8

Moises et al., linkage, p<0.01

Coon et al., LOD 2.1

Vallada et al., LD p<0.001

Sz Collaborative Linkage Group, LD, p<0.0009

}VCFS

GPCR

arrestin

PP

GPCR

PP

Endocytosis

arrestin

Agonist

PP GRK3

GPCR

HeLaCortex

50X G3 50X G350X P5 50X P5

Sp4 -Sp1

G3 G3 G3 G3 G3 G3 G3P5P5 P5 P5 P5 P5 P5 P5G3

0123456789

WT P5

x1

00

00

0

hGRK3 SNP P5 in mouse cortical neurons

Zhou 2008, Biological Psychiatry

Bipolar

Schizophrenia

1 2 3 4 5 6 7 8 9 10 11

12 13 14 15 16 17 18 19 20 21 22 X Y

Association has greater power to detect genes of small effect

Common disease – common variant

Screen entire genome with high density of markers◦ Microarray based technologies◦ Large number of SNPs

identified by HapMap◦ 1M SNPs now routinely run

Little power if many rare SNPs of strong effect

Study Type Sample Platform Results

WTCCC / Craddock

Case control

2000/3000

Affy 500K PALB2, p=10-8

STEP-BD/ Sklar Case control

1461/2008

Affy 500K MYO5B; TSPAN8 p=10-8

CACNA1C (WTCCC)

W1-4 + German / Baum

Pooling 500/500800/800

Illumina 550K

DGKH; p=10-8

W1-4Scott / Pritizker

Pooling + ind GTing

1203/729 Illumina 550K

MAN2A1; p=10-7

German consortium / Cichon

Case control

702/1396 Illumina 550K

Chr 1??? p=10-7

Limited success to date Inadequate sample size

◦ Diabetes 2 required meta-analysis of over 15,000 cases Is the CDCV model wrong? Are there instead numerous rare strong

mutations? What role does Copy Number Variation play? Meta-analysis of all bipolar GWAS data worldwide

is now underway

New understanding of basic pathophysiology Reduction of stigma New methods of diagnosis

◦ New classification of disease based on pathophysiology◦ May subdivide or cut across behavioral definitions of

disease New medications to novel targets Pharmacogenomics Gene therapy Ethical issues of risk testing

Chip based assay of hundreds of SNPs

DNA provided by sputum or blood

Symptoms and Genes

Biology BasedDiagnosis

Prognosis Medication Response

Genes explain about 65% of the cause of bipolar disorder

Affective temperaments and bipolar spectrum disorders are genetically related to bipolar disorder

Some bipolar genes likely play a role in other psychiatric disorders

Numerous genes likely interact to produce the spectrum of bipolar related traits

GWAS promises the discovery of many new genes The discovery of the genes will lead to a new system

of diagnosis and new more specific treatments

San DiegoTom BarrettNik Schork Xian Jin ZhouRichard Hauger Mark GeyerHagop AkiskalTiffany Greenwood Tatyana ShektmanBecky McKinney

CincinnatiPaul KeckSue McElroy

VancouverRonald RemickDessa Sadovnick

IrvineAnne Spence

TorontoJim KennedyEmanuela Mundo

NIMH Genetics Initiative for Bipolar DisorderJohn NurnbergerJohn RiceElliot GershonWilliam ScheftnerWilliam CoryellWade BerrettiniJimmy PotashFrancis McMahonMelvin McInnisWilliam Byerley

How does genetics help clarify the relationship between the different presentations of the bipolar spectrum?◦ Family epidemiology?◦ Molecular studies?

How might genes cause these varied presentations?

How are genes mapped? What is GWAS and how might it help?

How might DNA testing be used in psychiatry? Would you use it in your practice? What would be the advantages? What would be the concerns? When will it be ready? Should we do risk testing? What would we do with the results of risk testing?