Genetics of Schizophrenia

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Genetics of Schizophrenia

• Jon McClellan, MD
• University of Washington
• Disclosures Grants from NIH, Stanley Medical
  Foundation, NARSAD
• No Industry Sponsored Research, Speakers Boards,
  or Consultation

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Schizophrenia Genetics

• Until recently, most widely quoted model in
  Psychiatric Genetics
• Common Disease Common Allele Model
• Polygenic model
• Combined impact of common genetic variants, each
  with small effect on risk, plus interactions with
  environmental risk factors, results in the
  illness

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• Common Disease Rare Variants Model
• Rare large effect mutations are responsible for
  substantial portion of schizophrenia, autism, and
  perhaps most complex illnesses
• Individual mutations may be specific to single
  cases or families
• Many different genes involved, each with many
  different disease-causing mutations
• Human disease characterized by enormous genetic
  heterogeneity
• McClellan and King, Cell 2010

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How can Rare Mutations Explain a Common
Psychiatric Disorder?

• The majority of human genes are involved with
  brain development
• New mutations are common
• Those that cause illnesses may only persist a few
  generations because of their negative
  consequences
• Any gene important to an illness may be disrupted
  by 1000s of different mutations
• Each mutation may be rare, but collectively the
  gene may be responsible for a substantial portion
  of cases (BRCA1)
• Different mutations in different genes may
  disrupt related neurobiological pathways, leading
  to the same disorder

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• Genetic causes of complex disease must reflect
  evolutionary forces shaping the human genome

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Human Migration
Adapted from Cavalli-Sforza Feldman, Nature
Genetics  33, 266 275, 2003
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A village of a few hundred families, anywhere.
What of all human variation is
here? 10 50 80 90
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Human Genetic Diversity
Adapted from Tishkoff Verrelli Annu Rev
Genomics Hum Genet 2003
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Human Allelic Heterogeneity

• The exponential growth of the human population
  has resulted in a vast number of new mutations
• All possible mutations have occurred and will
  occur again
• Each person harbors 175 de novo mutations
• Recent alleles usually rare and specific to one
  population (or even one family)
• Many are deleterious and do not persist beyond a
  few generations

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Schizophrenia and Autism Caused by recent rare
large effect mutations?

• Illnesses persist with similar prevalence
  world-wide
• Familial Disorder, yet most cases sporadic
• Persistence of Illness Despite Impact on
  Fertility
• Environmental Exposures
• Increased Risk associated with Paternal Age
• Maternal Famine for Schizophrenia

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Schizophrenia and Parental Age
Malaspina et al., Arch Gen Psychiatry 2001
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Reichenberg et al., 2006, Arch Gen Psychiatry
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Dutch Hongerwinter 1944-45
Susser et al. Arch Gen Psych 1996
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Chinese Famine of 1959-60
Wuhu region of Anhui Province
St. Clair et al. JAMA 2005
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Rare Structural Variants Disrupt Multiple Genes
in Neurodevelopmental Pathways in
Schizophrenia Tom Walsh, Jon M. McClellan, Shane
E. McCarthy, Anjené M. Addington, Sarah B.
Pierce, Greg M. Cooper, Alex S. Nord, Mary
Kusenda, Dheeraj Malhotra,Abhishek Bhandari,
Sunday M. Stray, Caitlin F. Rippey, Patricia
Roccanova, Vlad Makarov, B. Lakshmi, Robert L.
Findling, Linmarie Sikich, Thomas Stromberg,
Barry Merriman, Nitin Gogtay, Philip Butler,
Kristen Eckstrand, Laila Noory, Peter Gochman,
Robert Long, Zugen Chen, Sean Davis, Carl Baker,
Evan E. Eichler, Paul S. Meltzer, Stanley F.
Nelson, Andrew B. Singleton, Ming K. Lee, Judith
L. Rapoport, Mary-Claire King, Jonathan Sebat3
Science, 320539-43, 2008
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Study Ties Genetic Variations to Schizophrenia

• "You're basically screwing up the way that the
  regulation of brain growth occurs"
• Jon McClellan, MD
• Dad, "screwed up" is not a very professional
  phrase, it makes you sound kind of stupid
• Tessa McClellan

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Hypothesis

• Rare copy number mutations affecting genes in
  neurodevelopmental pathways will be more common
  among persons with schizophrenia than among
  controls

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Subjects
Cases 150 persons with schizophrenia or
schizoaffective disorder Controls 268 persons
age gt35 Free of signs of neurological or
psychiatric illness Same distribution of
self-reported ethnicities as cases
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Copy Number Variants
Deletions
Duplications
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Copy Number Variants

• Deletions, duplications and inversions of DNA
• Can involve thousands, or even millions, of
  basepairs
• Most Copy Number Variants are benign and common
• Copying errors that disrupt normal gene function
  can lead to disease.
• Sebat et al., 2004

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• Definition of Rare CNVs
• Not previously reported in Database of Genomic
  Variants (DGV)
• Data from 1000s of individuals
• CNV found either only in cases or only in
  controls
• Mutation impacts one or more genes
• 100kb or larger in size

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Subset of Rare structural variants detected using
high density array CGH
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Rare Structural Variants and Schizophrenia

• Individuals with Schizophrenia significantly more
  likely to have a rare deletion or duplication (
  100 kb) impacting a gene
• 15 vs 5 of healthy controls
• Rate of rare mutations higher in early onset
  cases (20)
• Each mutation was different, and impacted
  different genes
• Genes disrupted in Schizophrenia cluster in
  pathways related to neurodevelopment, including
  glutamate and neuregulin pathways
• Walsh et al., Science, 2008

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• So
• What about other studies?

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• Enrichment of Rare Structural Variants replicated
  by several independent groups
• 8-fold increased risk of de novo structural
  mutations in Sporadic Schizophrenia (Xu et al.,
  2008)
• Higher frequency of rare duplications and
  deletions found in large samples of patients with
  schizophrenia (Stefansson et al., 2008
  International Schizophrenia Consortium, 2008)
• Recurrent mutations at genomic Hotspots found
  in multiple cases
• Several-fold increased risk for disorder (ORs gt
  5)

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Genomic Hotspots
Nonallelic Homologous Recombination due to
Segmental Duplication
Genomic Hot Spots
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ISC Nature 2008
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• Genomic Hotspots (so far)
• 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p12.1,
  16p13.11, 17p12, and 22q11.2
• Duplications in the neuropeptide receptor VIPR2
• And with better sequencing tools
• Rare deleterious point mutations and indels
  detected in genes important to neurodevelopmental
  pathways
• e.g., GRM1, MAP1A, GRIN2B, and NLGN
• Critical pathways include glutamate functioning,
  synapse formation, signaling and brain
  development
• Both rare De novo and inherited events may cause
  the disorder

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Genomic Analysis of Schizophrenia
(GENESIS) R01MH083989
NIMH series gt5000 cases, family members gt5000
controls Raquel Gur, MGI, U Pennsylvania David
Braff, COGS, UC San Diego Robert Savage,
PAARTNERS, U Alabama Vish Nimgaonkar, GSS, U
Pittsburgh Genomic sequencing and analysis, U
Washington, Seattle Tom Walsh, Jack McClellan,
Ming K Lee, Anne Thornton, Amanda Watts, Sunday
Stray
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Genomic Analysis of Schizophrenia
(GENESIS) Identification of de novo events
Trios with sporadic schizophrenia Affected
proband and unaffected parents Negative family
history of schizophrenia, bipolar disorder, or
major depression
Exome sequencing of proband and both parents
from blood-based DNA
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Genomic Analysis of Schizophrenia (GENESIS)
Eventually 300 trios, presently 92 trios in
pipeline
First 22 trios 19 validated de novo mutations
in 19 different genes
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Strong Association of De Novo Copy Number
Mutations with Autism Jonathan Sebat, B.
Lakshmi, Dheeraj Malhotra, Jennifer Troge,
Christa Lese-Martin, Tom Walsh, Boris Yamrom,
Seungtai Yoon, Alex Krasnitz, Jude Kendall,
Anthony Leotta, Deepa Pai,1 Ray Zhang, Yoon-Ha
Lee, James Hicks, Sarah J. Spence, Annette T.
Lee, Kaija Puura,6 Terho Lehtimäki, David
Ledbetter, Peter K. Gregersen, Joel Bregman,
James S. Sutcliffe, Vaidehi Jobanputra, Wendy
Chung, Dorothy Warburton, Mary-Claire King, David
Skuse, Daniel H. Geschwind, T. Conrad Gilliam,
Kenny Ye, Michael Wigler
Science, 316445-449, 2007
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Rare Structural Variants and Autism

• 10 of Individuals with Sporadic Autism have de
  novo duplications and deletions (gt 100kb, Sebat
  et al., 2007)
• 2 of multiplex cases
• 1 of controls
• 7 of cases with Sporadic Autism vs 2 of
  multiplex cases have de novo CNVs (Marshall et
  al., 2008)
• Replicated several times by independent groups

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Rare Mutations and Autism

• Genomic Hotspots
• 1q21.1, 7q11.23, 15q13.3, 16p11.2, 16p13.11,
  17p12, and 22q11.2
• 16p11.2 may explain 1 of cases

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Rare Mutations and Autism

• To date, rare deleterious mutations associated
  with Autism in gt 100 genes and gt 40 genomic loci
• Genes disrupted associated with pathways critical
  for neurodevelopment, including synaptic
  development, neuronal cell-adhesion and ubiquitin
  degradation
• Many of the same genes and hotspots are also
  associated with Schizophrenia

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Rare Variants and Psychiatric Disease

• Rare CNVs, point mutations and indels also
  reported for
• Intellectual Disability
• Tourette Disorder
• ADHD
• Bipolar Disorder
• Some mutations/genes same as those found in
  Schizophrenia
• Includes Genomic Hotspots

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Genomics and Psychiatry

• Autism, Schizophrenia , Intellectual Disability,
  Bipolar Disorder, ADHD and Tourette Disorder each
  associated with rare deleterious mutations that
  disrupt genes related to brain development
• Many disease specific mutations appear to be
  either de novo, or of recent origin
• Genes implicated involved in neural development

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Genomics and Psychiatry

• Most individuals have a different mutation
  involving different gene(s)
• Genomic Hotspots may account for a higher
  proportion of cases
• Some individuals are found to have more than one
  deleterious mutation in different genes/loci
• Multi-hit model explains how some events are
  inherited from nonaffected persons
• Adds further complexity to heritability of
  disorders

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Same Gene, Different Disorder
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Blackwood et al., 2001 AJHG
DISC1
18/29
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Different Gene(s), Same Disorder
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16p13.11
Developmental Delays ADHD Autism Schizophrenia
1q21.1
16p11.2
Macrocephaly Developmental Delays Autism
Developmental Delays Autism Schizophrenia Bipolar
Disorder
Developmental Delays Epilepsy
Microcephaly Developmental Delays Schizophrenia
Developmental Delays Autism
Developmental Delays Autism Schizophrenia Epilepsy

22q11.2
15q13.3
Developmental Delays Autism
Developmental Delays
Developmental Delays ADHD Autism Schizophrenia Bip
olar Disorder
Developmental Delays Autism Schizophrenia Epilepsy
NRXN1 CNTNAP2
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• Meanwhile.
• The search for common risk alleles
• Genome-wide Association Studies (GWAS) struggle
  with
• Lack of replication
• Small dwindling effect sizes (lt 1.5)
• Lack of demonstrated biological relevance for
  disorder

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• Neuropsychiatric disorders characterized by
  marked genetic heterogeneity
• Most affected individuals may have a different
  genetic cause
• Multiple different mutations in multiple
  different genes/genomic loci may ultimately act
  by disrupting neuronal homeostasis (Ramocki
  Zoghbi, 2008)
• Phenotypic differences may be due to timing and
  impact of mutation on development, plus other
  epistatic, epigenetic and/or environmental
  factors

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So

• Psychiatric diagnoses have clinical marked
  heterogeneity
• and
• Marked genetic heterogeneity characterizes most
  complex illnesses
• Vast clinical and genetic heterogeneity likely
  explains why diagnostic issues are so complex and
  treatment response so variable across individuals
  with the same illness

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Implications

• DSM diagnostic categories may be too
  heterogeneous for major advances in
  neurobiological understanding of disorders
• Research needs to focus on individuals grouped by
  disrupted neurobiological pathways/genes rather
  than by broadly defined syndromes

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University of Washington Mary-Claire King Tom
Walsh Jack McClellan Sarah Pierce Cait
Rippey Diane Dickel Sunday Stray Ming K.
Lee Greg Cooper Carl Baker Evan Eichler Cold
Spring Harbor Laboratory Shane McCarthy Abishek
Bhandari Mary Kusenda Dheeraj
Malhotra Jonathan Sebat
NIH - NIMH Anjene Addington Judith
Rapoport NIH - NIA Andrew Singleton