Pharmacogenomics - Bipolar disorder

personalised drugs based on genetic makeup
1. knowledge of genetic origin of disorders
  1. not straightforward - ecogenetics + epigenetics
  2. DNA mutations - mostly spontaneously/ not mutagens
    1. submicroscopic changes in one or more nucleotides (SNPs)
      1. dynamic (unstable) mutations
      2. fixed (stable) mutations
    2. copy number variation (CNV)
      1. new type - loss of large chunks of DNA sequence from the genome (10.000 - 1 million letters)
    3. Strucrural effects on proteins: subdivided to synonymous - non-synonymous
    4. Functional effects on proteins: phenotypic effect through either loss or gain of function
    5. dominant-negative mutations: mutant genes in the heterozygous state -> loss of protein activity or function. Common in structural proteins such as collagens
2. improvement in drug discovery - easier to find therapeutics
3. better safer drugs - less adverse drug reactions
4. advanced warning through early screening - overall decrease in cost of health care
Bipolar disorder
1. 3 main types of BD
  1. Bipolar I disorder: 1 or more manic or mixed episodes + major depressive episode
  2. Bipolar II disorder: 1-2 major depressive episodes + 1 hypomanic episode
  3. Cyclothymic disorder: 2 years of hypomanic periods that do nt meet the criteria for the other disorders
2. Current treatments
  1. Limited to lithium and valproic acid
  2. cannot be matched with specific disease subtypes
  3. 1/3rd of the patients -> unresponsive and experience unacceptable side effects
3. locus identification - genetics
  1. clearly genetic conditions - family history greatest risk factor
  2. overall heritability of the bipolar spectrum is 0.71
  3. Concordance rate between identical twins of 60-70%
  4. Non-mendelian inheritance
  5. variable age of onset
  6. Genetic heterogeneity (many genes can cause the illness, phenotypic variation)
  7. oligogenic/polygenic causation - more than one gene required to produce phenotype
4. Characteristics
  1. Characteristics: mood swings between mania and depression which can last over several weeks or more
  2. Prevalence of around 2.4% worldwide with higher % in USA and New zeland
    1. Merikangas et al 2011
  3. Increased mortality rates in people with BD by suicide
Benefits of gene identification
1. Understand aetiology
2. Improved drug development + testing
3. development of definitive diagnostic tests
4. Identify individuals with high risk alleles (prophylaxis
5. Understanding of interaction with non-genetic risk factors
6. insight into normal brain development and function
Research
1. GWAS: genome-wide association studies
  1. identify loci that increase risk of disease
  2. identify loci that predict treatment response
  3. output -> manhattan plot: depicts several associated risk loci
    1. each dot is an SNP, X axis is genomic location and Y location is association level
2. Mood stabilisers - lithium
  1. alda scale for response to lithium
  2. prevents relapse of mania and depression, many patients unresponsive
  3. Two SNPs located 7.2kb apart in the introns of the gene encoding glutamate decarboxylase-like protein I (GADLI) showed the strongest association
    1. Chen et al (2014)
    2. ++highest sensitivity and specificity for lithium were 93% and 85% for rs17026688 and 93% an 86% for rs17026651, respectively
      1. Chen et al (2014)
3. GWAS for bipolar risk
  1. 1.8 millions tested in thousands of cases (4k+) and controls (6k+)
  2. ANK3 variation confers risk of bipolar disorder in three independent datasets
    1. ANK3: adaptor protein at axon initial segments that regulates the assembly of voltage-gated sodium channels
    2. Calcium channel subunit (CACNAIC) is associated with bipolar disorder
    3. ANK3 and subunits of the calcium channel are down-regulated in response to lithium in rat brain
    4. maybe BD in part an ion channelopathy ++
    5. Ferreira MA et al (2008)
Animal models - the myshkin mouse model of Mania
1. association between bipolar disorder and SNPs in NA+, K+ - ATPase a1, a2 and a3 genes
  1. maintains and restores NA+ and K+ electrochemical gradients across the cell membrane - necessary for prolonged periods of correct neuronal function
    1. consumes 40-50 of total brain ATP. catalytic a subunit and regulatory beta subunit
2. reduced a3 mRNA in prefrontal cortex and a2 mRNA in temporal cortex
3. digitalis (inhibitor) toxicity can be accompanied by manic and depressive symptoms in healthy humans
4. normal expression and cellular distribution of Myshkin mutant NA+/K+ - ATPase a3
  1. causes 36-42% reduction in total NKA activity in Myk/+ brain
  2. Myk/Myk die soon after birth
5. open field: locomotor activity in response to novelty
  1. BD test subjects hyperambulate in a novel environment
    1. Young et al (2007)
  2. Hyperambulation is reduced by mood stabilisers
    1. Kirshenbaum et al (2011)
6. increased sensitivity to amphetamine - not as good a model for ADHD
  1. Kirshenbaum et al (2011)
7. Exhibits decreased anxiety (increased risk taking) - core symptoms of mania
  1. reduced by mood stabilisers
    1. Kirshenbaum et al (2011)
8. increased response for naturally rewarding stimulus
  1. Kirshenbaum et al (2011)
9. prepulse inhibition and startle habituation deficits
  1. Kirshenbaum et al (2011)
10. Sleep and REM latency reduced in Myshkin - as in most individuals with BD
  1. Behavioural circadian period is increased
    1. Kirshenbaum et al (2011)

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