Genetics of Psychiatric Disorders

Genetics of Psychiatric Disorders Francis J. McMahon, MD National Institute of Mental Health* *views expressed do not necessarily reflect the policy ...
Author: Hilary Little
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Genetics of Psychiatric Disorders Francis J. McMahon, MD National Institute of Mental Health*

*views expressed do not necessarily reflect the policy of the US government

Psychiatric disorders  

 

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A major cause of morbidity and mortality worldwide The main risk factor for suicide, the leading medical cause of death in adolescents and young adults and a major cause of death and disability in the elderly Often under-recognized and misdiagnosed The major disorders are all highly heritable

Lifetime Prevalence of Mood Disorders ECA Data, 1986 Lifetime Prevalence (%) ….

14 12 10 8 6

Men Women

4 2 0 Bipolar I

3

Bipolar II

Major Dysthymia Depression Diagnosis

Total

Weissman, et al. 1986

Mood Disorders are Highly Heritable Fraternal Twins

Identical Twins mood disorder no disorder

35% 67%

Heritability = 80%

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The Danish Twin Study (Bertelsen et al. 1977)

Mood Disorders are Familial Major Affective Disorders Among Relatives of Affected and Unaffected Probands

Proband's Diagnosis

UNAFF UP BPI BPII SA

Gershon et al 1982

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0 10 20 30 40 Lifetime Prevalence (%) of Major Affective Disorders in Relatives

The Familiality of Mood Disorders has a Genetic Basis Rates of Affective Disorder in Biological Parents 35% 32% 30% 26% 25% 20% 15% 10% 5% 5% 0% Non-Adoptees Adoptees with Adoptees with Bipolar Bipolar Disorder without Bipolar Disorder Disorder

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Mendlewicz & Rainer 1977

Several Genes Contribute to Psychiatric Disorders One Gene

One Disease Clinically variable 7

Several Genes

Many Diseases Some clinically similar

Some Methods of Molecular Genetic Investigation  Linkage

studies

 Association

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studies

 Studies

of gene expression

 Genetic

modeling

Some Linkages in Bipolar Disorder

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Chromosome 6

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Adapted from McQueen et al. 2005

Genes Associated with Mood Disorders in Several Studies

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Genome-wide Association Linkage/Candidate Genes

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Collins, 2006

Genome-wide association studies 

Bipolar disorder  



Schizophrenia  



underway

ADHD 

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2 published studies Several underway

Major Depression 



3 published studies At least 2 underway

underway

Significant GWAS Findings as of 9/08 Bipolar Disorder

ANK3

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Significant GWAS Findings as of 9/08 Schizophrenia

-rs4129148

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Rare Alleles 

 

Rare mutations and copy number variants may play a role in several common disorders Interesting findings to date in autism Replicated findings in schizophrenia   

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Deletion of 1q21.1 Deletion of 15q13.3 Deletion of 22q11 (VCFS)

Open Questions 





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What is the relative role of common and rare variants in psychiatric disorders? How much of the high familial risk of psychiatric illness can be accounted for by the findings to date? (little) Will the genetic findings finally shed light on etiologic pathways?

How Genetic Discoveries will Affect Clinical Psychiatry  

  

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Better diagnostic methods Improved treatment planning New insights into causes, both genetic and non-genetic Identification of high-risk individuals suitable for primary prevention efforts Potential for novel - even curative - therapies

New ways to validate our system of diagnostic classification in psychiatry 





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Shift in emphasis from mere reliability to validity based on shared biology Clinically similar disorders may reveal distinct genetic contributions and distinct biology, leading to diagnostic splitting Clinically distinct disorders may be shown to share genetic determinants

Model: Spino-cerebellar Atrophies Five Classical Types Many distinct genetic forms

Three Pathophysiologic Groups Polyglutamine disorders Channelopathies Gene expression disorders 20

Margolis 2003

Improved Treatment Planning • Greater diagnostic homogeneity may lead to more predictable responses to available treatments • Genetics may illuminate brain pathology at the molecular level, facilitating the development of novel, “designer drugs” • Identification of people who are most likely to benefit or suffer serious side effects from an available treatment 21

Predicting outcome of antidepressant treatment Rate of definite non-response

Marker alleles

0% Overall

n = 1358

HTR2A, any

n = 1162

GRIK4, both

n = 239

BCL2, any

n = 193

HTR2A, both

n = 440

HTR2A*and GRIK4*

n = 34

HTR2A*and BCL2

n = 39

BCL2 and GRIK4 *

n = 26

None

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10%

*both

n = 127

20%

30%

40%

 maximum risk reduction 28% 

McMahon et al. 2005; Paddock et al. 2007

A Window into Non-genetic Causes 

 

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Genes account for more than half of the individual differences in risk for psychiatric disease - by far the single biggest factor What accounts for the rest? Follow-up study of carriers of high-risk genes - what is different about people who do not fall ill?

Genotype and Life Events Interact to Increase Risk for MDD *

informant-report

**

*

LPR x LE

**

Life Events

measure

suicide

SERT-LPR

**

diagnosis

*

self-report

**

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0

1

2

** 3

4

score statistic

5

6

Caspi et al., 2003

Potential for Prevention  





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Carriers of high-risk genes will for the first time be identifiable in the population They may benefit from psychotherapy and other interventions aimed at preventing mental illness The efficacy of such primary prevention will for the first time be testable by long-term study of high-risk groups Large potential impact on public health - most mentally ill never see a psychiatrist

Genetic Attributable Risk 





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Genetic attributable risk - the proportion of ill people who would not be ill if they did not carry a particular susceptibility allele. Alleles that have a small impact on disease risk can have a large attributable risk when the alleles are common The clinical impact of genetic discoveries in psychiatry is expected to be large, even if the clinical impact of the individual alleles is not.

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A role for genetic testing? 

Diagnosis  

A distant horizon in psychiatry Unlikely to have strong predictive value  



Treatment -

-



May be very helpful for identifying cases most likely to suffer serious side effects or fail to respond This is beginning to happen in other fields of medicine

In General -

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individual genes confer too little risk conferred risks may be relatively nonspecific

Simultaneous testing of many genes will probably be necessary Judicious use of genetic tests will be critical

Don’t Forget the Family History! “The importance of the family history will only be enhanced in the future. Even when an individual’s genome can be displayed on a personal microchip, interpreting that information will depend in large part on the biological and environmental contexts in which that genome is expressed.” -Pyeritz, 1997 (as quoted in Bennett 1999)

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Role for Clinicians 





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Need to stay abreast of research developments Need to interpret these developments for patients and their families Unique and essential roles psychiatrists, pharmacists, and other clinicians

Conclusions 







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Genetic approaches to psychiatric disorders hold great promise for improved diagnosis, treatment, and understanding of etiology Genetic discoveries are finally beginning to role in and may soon have an impact on our understanding of pathophysiology DNA diagnosis in psychiatry is problematic, but genetic tests may have a role in treatment planning in the future Clinicians will need to interpret genetic findings for patients and their families

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