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Genetics of Bipolar
Disorders
WADE BERRETTINI, MD, PhD
Karl E. Rickels Professor and
Director, Center for
Neurobiology and Behavior,
University of Pennsylvania
[email protected], 215-8980092
William Styron (author): “Mysteriously, and in ways
that are totally remote from natural experience, the
gray drizzle of horror induced by depression takes on
the quality of physical pain… The pain is unrelenting,
and what makes the condition intolerable is the
foreknowledge that no remedy will come---not in a
day, an hour, a month or a minute. It is hopelessness
even more than pain that crushes the soul…One does
not abandon, even briefly, one’s bed of nails, but is
attached to it wherever one travels."
Theodore Roethke (poet):
“For no reason I started to feel very good. My mind
raced. I didn’t sleep much. Suddenly I knew how to
enter into the life of everything around me. It was a
wonderful feeling. I passed a diner and all of a sudden
I knew what it felt like to be a lion. I went into the diner
and said to the counterman, “Bring me a steak. Don’t
cook it. Just bring it.” So he brought me this raw
steak and I started eating it.”
Principles for Psychiatric Genetics
Current categorization of psychiatric illnesses defines
separate syndromes (eg, bipolar disorder and schizophrenia)
as distinct, non-overlapping entities, despite the fact that
they share clinical characteristics and genetic liability.
Genetic risk for psychiatric disorders is polygenic, meaning
that hundreds to thousands of DNA variants (alleles) from
hundreds of genes may contribute risk alleles for a given
category of illness. Each common allele will have a small
effect on risk.
Rare alleles may have large effects on risk.
Both rare and common variants will explain fractions of the
genetic liability for psychiatric disorders. Rare variants may
have substantial effects on risk.
BPD & SZ Share Characteristics
CHARACTERISTIC
Onset in young adulthood
Men & women at equal risk
Occur at ~1% across the world
Higher risk for suicide
Chronic, episodic course
Hallucinations and/or delusions
Cognitive deficits
Increased risk for drug addiction
Treated by atypical antipsychotics
Elevated risk for MDD in relatives
Heritability estimate of ~80%
BPD
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+
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+
SZ
++
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+
+
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+
Disrupted in SZ 1 (DISC1)
♦  A
large kindred segregating multiple
psychiatric phenotypes has a
translocation (1;11)(q42;q14.3) which
was present in many affecteds but
generally not in well relatives (Blackwood
et al, AJHG 2001).
♦  The
translocation breakpoint disrupts
a gene, DISC1 and was also
associated with a decreased
amplitude and delayed latency of an
EEG-detectable event potential, the
P300.
DISC1 in SZ: the pedigree
RUP
RUP
10 RUP cases
1 BP case
7 SZ cases
BP
SZ
Copy Number Variations (CNVs) in SZ
Genome-wide association studies of SZ have
been used to detect CNVs, and several are found
at 10-fold (or higher) increased frequency in cases.
These CNVs are rare & have limited penetrance.
(Vassos et al, Hum Mol Genet, 2010)
The human genome includes
~ 3 billion base pairs of DNA,
in 23 pairs of chromosomes.
A gene is a DNA sequence
which encodes a protein. A
typical gene is 20,000 base
pairs in length.
An allele is a variation in DNA
sequence. The most common
DNA variation in the genome
is the single nucleotide polymorphism (SNP). There are
3,000,000 common SNPs in
the human genome.
Allele 1
Allele 2
CTAGTC
CTATTC
GATCAG
GATAAG
In the SNP example above,
the 4th base pair is G:C or T:A
The functional importance of
most SNPs is unknown.
ADVANCES in DNA TECHNOLOGY
~1,000,000 SNP CHIPs provide the ability
to obtain a genotype at 1 SNP every ~
3000 base pairs in the genome, allowing
determination of most common SNPs.
Allele-specific fluorescently-tagged DNA
fragments (known as oligonucleotides)
are mounted on the slide. The
oligonucleotides are sequence-specific
for one of the two alleles of a given SNP.
The fluorescent tag will emit energy at a
specific wavelength (color), only in the
presence of the specific SNP allele for
which they have been designed.
If this genotyping is done for 1000’s of
cases and 1000’s of controls, at every
common SNP it can be determined
whether an allele is more common among
cases than controls.
CACNA1c
0 1
2
3
4
5
6
7
8
-log10(pvalue)
9 10
BPD Genome-Wide Association Results
1 
2
3
4
5
6 7 8 9 10 11 12 13 14 16 18
10 20 22
Chromosomes
15 17 19 21
CACNA1C: A BPD Risk Gene
w  An L-type calcium channel gene, alpha 1C
subtype
w  Mutations in CACNA1C cause Timothy
Syndrome, including autistic features and
abnormal heartbeats.
w  The CACNA1C gene produces a protein which
binds lamotrigine (Lamictal) a medication
approved to treat bipolar disorder.
Nature , 2014
♦  GWAS
of 36,000 cases and 105,000
controls.
MHC locus
108 genomic regions implicated in
Genetic risk for SZ. Many of these
Have biologic support (eg, studies in
post mortem SZ brain reveal
abnormalities in mRNA and/or protein.
Mir 137
CACNA1c
Genomic sequencing results for 5303 MDD cases and 5337
controls of Chinese ethnicity (Nature, 2015). When analysis
was restricted to melancholia cases (4509), significance
increased by 2 orders of magnitude at the SIRT1 locus to 10-10
SIRT 1
LHPP
LHPP: phospholysine phosphohistidine
inorganic pyrophosphate phosphatase
♦  Very
little known!
♦  SIRT1: Sirtuin 1
♦ 
an evolutionarily conserved NAD(+)dependent histone deacetylase that is
necessary for caloric restriction-related
lifespan extension. SIRT1, as an intracellular
energy sensor, detects the concentration of
intracellular NAD(+) and uses this
information to adapt cellular energy output to
cellular energy requirements
Nature Genetics, 45:984, 2013
1. GWAS data for SZ, BPD, RUP, autism & ADHD were compared
to determine whether alleles nominally significant (!) in one
illness were also nominally significant in any other disorder.
2. But, each of these GWAS reports contains > 106 alleles,
so 5% (50,000) of these alleles are nominally significant in each
GWAS randomly (they are false positives).
3. There is no method to determine which are true positives.
Shared Alleles Across Multiple
Diagnostic Entities
*Consistent with
family studies
^Inconsistent
with family studies
^
* * * *
^ ^ ^
Reasons to Use Lithium Prophylaxis in BPD Blood levels are a check on compliance. Good tolerability Specific effect to reduce suicide. Less adverse metabolic effects than many other FDA-­‐approved treatments. •  Efficacy established through 50 years of study. • 
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Lithium PGX in Bipolar Disorder (Mertens et al, Nature, 2015) BPI pa@ents on lithium as the sole psychotropic were followed every 3 months to ensure euthymia for 2 years. Those who remained well were termed lithium responsive (LR). Pa@ents who relapsed to mania or depression were deemed lithium NR. Skin biopsies were taken to create iPSC-­‐derived cultured neurons. Neurons from BPI pa@ents were hyperexcitable, with greater numbers of spontaneous and evoked ac@on poten@als, increased expression of genes related to depolariza@on and reduced thresholds for ac@on poten@al genera@on. SUMMARY
BPD, MDD and SZ may not be completely
separate entities, sharing genetic risk
alleles.
♦  DISC1 and CACNA1c are susceptibility
genes for BPD and SZ.
♦  Most of the genetic risk for BPD and SZ
remains unexplained.
♦  The identified rare and common DNA
variants explain some of the genetic risk.
♦  Risk genes, in general, will not be specific
to a given diagnostic category, and our
current definitions of these illnesses must be
♦ 
re-written.