bipolar_disorder by wanghonghx

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


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


 TOTAL                    95/146        65.0   39/278        14.0
Spectrum disorders are partially genetically distinct
            Twins are partially concordant for polarity
                         Concordance in Monozygotic Pairs
                       Polarity

                       BP-BP               14
                       UP-UP               11
                       BP-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             61
      Bipolar II    3.0         30.3            63.6
      Non-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)
                                      *

    *       **
*                             *


        *   Significantly different from control rate
                                                        Tsuang 1980
Proband           Co-twin           MZ            DZ            MZ            DZ
                                    concordance   concordance   correlation   correlation
                                    (%)           (%)
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
                A                               B



   A   A                           B   B


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




                                         Affective Temperaments


                                              Major depression

                                                Bipolar II
                                                   Bipolar I

                                                    Schizoaffective Disorder

                                                             Schizophrenia




                       More Psychosis Genes
                                            Primary genetic
                                             transmission
Population Frequency




                                               More fit




                                                                  Less fit




                       More Bipolar Genes   Hyperthymia   Bipolar Disorder
      Gene B
                                     Spectrum
                                   temperaments
Bipolar 1
                        Unipolar
             Gene A
  Gene D    Bipolar 3   Gene E




  Bipolar 2
       Gene C
                        Allelic Heterogeneity
                      Mutation B
                                                 Bipolar Disorder
                 X
Gene A
                      X                          Schizophrenia
                      Mutation S


                       Gene-gene interactions
                                            Bipolar Disorder
                      + Gene B
  Non-specific gene
                      + Gene S              Schizophrenia


                       Gene-environmental interactions
                                                Bipolar Disorder
                      + Environment B
 Non-specific gene
                                                Schizophrenia
                      + Environment S

                          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                      Resolution
               Linkage                       Microsatellite markers       5-20 Mb

               Association                   Single Nucleotide
Human Genome




                                             Polymorphisms (SNP)          5-25kb
   Project




               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 gene
                                            2. is associated with illness
                                             Genome Survey of 20 Bipolar Families
                    4
                                         1                                     2                                3                                     4
                    3
                    2
                    1
                    0
                         0         100        200                 300        400             500          600            700         800                   900     1000

                    4                5                                   6                                      7                               8
                    3
Maximum LOD Score




                    2
                    1
                    0
                      960                                  1160                                    1360                             1560
                    4
                               9                       10                          11                     12                   13                     14
                    3
                    2
                    1
                    0
                        1700                   1900                                2100                         2300                                2500
                    4
                               15                   16                  17                18               19                  20          21              22
                    3
                    2
                    1
                    0
                        2550                        2750                              2950                             3150                                 3350

                                                                  Genetic Distance (cM)
                            Chromosome 22
        Summary of results in Bipolar Disorder and Schizophrenia
               Locus
             D22S420
             D22S264          Bipolar Disorder
             D22S427
             D22S425
                              Schizophrenia


  13
             D22S539
             D22S303    }     VCFS
             D22S257
            D22S1174
             D22S315
            D22S1164          UCSD genome scan, LOD 2.2
             D22S926
11.2         D22S925          GRK3
             D22S421
             D22S419
                              NIMH GIBP consortium, LOD 2.5
11.1         D22S429
            D22S1144
             D22S689          Myles Worsley et al., LOD 3.5
11.22        D22S684
             D22S693          Detera-Wadleigh et al., NIMH intramural, LOD 2.5
12.1         D22S691
12.3         D22S1ju          UCSD genome scan, LOD 3.8
             D22S5ju
             D22S277          Moises et al., linkage, p<0.01
             D22S683
13.2         D22S278
            D22S1142          Sz Collaborative Linkage Group, LD, p<0.0009
             D22S283
13.32        D22S692          Vallada et al., LD p<0.001
            D22S1045
             D22S445          Pulver et al., LOD 2.8
             D22S307
             D22S270          Coon et al., LOD 2.1
             ata5f505
             D22S274
Agonist                       GPCR
                         PP
                                                     GPCR
          GPCR
                     
                         GRK3                                PP
                                         arrestin

                                                          
                                                                  Endocytosis

                                                          PP

                                              arrestin
          HeLa
                                                        Cortex


                                              a-Sp4      a-Sp1
           50X G3     50X P5                                       50X G3    50X P5

G3   P5    G3    P5    G3      P5   G3   P5   G3   P5      G3 P5   G3   P5   G3   P5                 hGRK3 SNP P5 in mouse
                                                                                                        cortical neurons
                                                                                                 9
                                                                                                 8
                                                                                                 7
                                                                                                 6




                                                                                       x100000
                                                                                                 5
                                                                                                 4
                                                                                                 3
                                                                                                 2
                                                                                                 1
                                                                                                 0

                                                                                                         WT               P5




                                                                                                       Zhou 2008, Biological Psychiatry
                1         2        3        4        5     6        7        8        9        10   11




Bipolar


Schizophrenia




                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 /             Case        2000/300   Affy 500K   PALB2, p=10-8
Craddock            control     0
STEP-BD/ Sklar      Case        1461/200   Affy 500K   MYO5B; TSPAN8
                    control     8                      p=10-8
                                                       CACNA1C (WTCCC)
W1-4 + German /     Pooling     500/500    Illumina    DGKH; p=10-8
Baum                            800/800    550K
W1-4                Pooling +   1203/729   Illumina    MAN2A1; p=10-7
Scott / Pritizker   ind GTing              550K
German              Case        702/1396   Illumina    Chr 1??? p=10-7
consortium /        control                550K
Cichon
   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
          DNA provided by sputum or blood


        Chip based assay of hundreds of SNPs


                Symptoms and Genes




Biology Based         Prognosis             Medication
  Diagnosis                                 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 Diego                Toronto
     Tom Barrett            Jim Kennedy
     Nik Schork             Emanuela Mundo
     Xian Jin Zhou       NIMH Genetics Initiative for
     Richard Hauger         Bipolar Disorder
     Mark Geyer              John Nurnberger
     Hagop Akiskal           John Rice
     Tiffany Greenwood       Elliot Gershon
     Tatyana Shektman        William Scheftner
     Becky McKinney          William Coryell
Cincinnati                   Wade Berrettini
     Paul Keck               Jimmy Potash
     Sue McElroy             Francis McMahon
Vancouver                    Melvin McInnis
     Ronald Remick           William Byerley
     Dessa Sadovnick
Irvine
    Anne Spence
   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?

								
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