Genetics of Schizophrenia
Jon McClellan, MD
University of Washington
Disclosures: Grants from NIH, Stanley Medical Foundation, NARSAD
No Industry Sponsored Research, Speaker’s Boards, or Consultation
Schizophrenia GeneticsUntil 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
“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
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 1000’s 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
Genetic causes of complex disease must reflect evolutionary forces shaping the human genome
Human Migration
Adapted from Cavalli-Sforza & Feldman, Nature Genetics 33, 266 – 275, 2003
A village of a few hundred families, anywhere.
What % of all human variation is here?
10%
50%
80%
90%
Adapted from: Tishkoff & Verrelli Annu Rev Genomics Hum Genet 2003
Human Genetic Diversity
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
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
1.00
1.50
2.00
2.50
3.00
< 30 30 - 35 - 40 - 45 - 50+
Parent’s age at childbirth
Paternal ageMaternal age
Rel
ativ
e ri
sk o
f S
chiz
oph
ren
ia
Schizophrenia and Parental Age
Malaspina et al., Arch Gen Psychiatry 2001
Reichenberg et al., 2006, Arch Gen Psychiatry
Birth month and year
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Jan-Jun1944
Jul-Dec1944
Jan-Sep1945
Oct-Dec1945
Jan-Jun1946
Jun-Dec1946
Sch
izop
hre
nia
(%
)
Dutch Hongerwinter 1944-45
Susser et al. Arch Gen Psych 1996
Chinese Famine of 1959-60
St. Clair et al. JAMA 2005
0.00
0.50
1.00
1.50
2.00
2.50
1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966
Sch
izo
ph
ren
ia (
%)
Wuhu region of Anhui Province
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, 320:539-43, 2008
“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
Hypothesis
Rare copy number mutations affecting genes in neurodevelopmental pathways will be more common among persons with schizophrenia than among controls
Subjects
Cases 150 persons with schizophrenia or schizoaffective disorder
Controls 268 persons age >35 Free of signs of neurological or psychiatric illnessSame distribution of self-reported ethnicities as cases
Copy Number Variants
Deletions
Duplications
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
Definition of Rare CNVs
Not previously reported in Database of Genomic Variants (DGV)
Data from 1000’s of individualsCNV found either only in cases or only in controlsMutation impacts one or more genes100kb or larger in size
del Chr2:211,792,494-212,191,651 del Chr3:7,177,597-7,314,117 del Chr3:197,224,662-198,573,215
del Chr5:36,190,704-36,693,387 dup Chr7:77,358,702-77,857,149 dup Chr8:142,025,432-142,393,948
dup Chr18:7,070,926-7,565,943 dup Chr19:59,045,962-59,363,706 del Chr22:32,048,581-32,715,286
Subset of Rare structural variants detected using high density array CGH
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
So…
What about other studies?
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 (OR’s > 5)
Genomic “Hotspots”
Nonallelic Homologous Recombination due to Segmental DuplicationGenomic “Hot Spots”
ISC Nature 2008
CasesN=3391
ControlsN=3181
13 0
0
1
9
10
22q11.2
(VCFS)
15q13.3
1q21
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
Genomic Analysis of Schizophrenia (GENESIS)
R01MH083989
NIMH series: >5000 cases, family members; >5000 controls
Raquel Gur, MGI, U PennsylvaniaDavid Braff, COGS, UC San Diego
Robert Savage, PAARTNERS, U Alabama Vish Nimgaonkar, GSS, U Pittsburgh
Genomic sequencing and analysis, U Washington, SeattleTom Walsh, Jack McClellan, Ming K Lee,
Anne Thornton, Amanda Watts, Sunday Stray
Genomic Analysis of Schizophrenia (GENESIS)
Identification of de novo events
Trios with sporadic schizophreniaAffected 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
First 22 trios:
19 validated de novo mutations in 19 different genes
Genomic Analysis of Schizophrenia (GENESIS)
Eventually 300 trios, presently 92 trios in pipeline
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, 316:445-449, 2007
Rare Structural Variants and Autism
10 % of Individuals with Sporadic Autism have de novo duplications and deletions (> 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
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
Rare Mutations and Autism
To date, rare deleterious mutations associated with Autism in > 100 genes and > 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
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
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
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
Same Gene, Different Disorder
Blackwood et al., 2001 AJHG
DISC1
18/29
Different Gene(s), Same Disorder
MacrocephalyDevelopmental DelaysAutism
MicrocephalyDevelopmental DelaysSchizophrenia
1q21.1
15q13.3
Developmental DelaysAutismSchizophreniaEpilepsy
Developmental Delays
16p11.2
Developmental DelaysAutism
Developmental DelaysAutismSchizophreniaBipolar Disorder
22q11.2
Developmental DelaysAutism
Developmental DelaysADHDAutismSchizophreniaBipolar Disorder
Developmental DelaysAutismSchizophreniaEpilepsy
NRXN1CNTNAP2
Developmental DelaysADHDAutismSchizophrenia
Developmental DelaysEpilepsy
16p13.11
Meanwhile….
The search for common risk alleles
Genome-wide Association Studies (GWAS) struggle with:
• Lack of replication
• Small dwindling effect sizes (< 1.5)
• Lack of demonstrated biological relevance for disorder
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
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
ImplicationsDSM 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
University of WashingtonMary-Claire KingTom WalshJack McClellanSarah PierceCait RippeyDiane DickelSunday StrayMing K. LeeGreg CooperCarl BakerEvan Eichler
Cold Spring Harbor LaboratoryShane McCarthyAbishek BhandariMary KusendaDheeraj MalhotraJonathan Sebat
NIH - NIMHAnjene AddingtonJudith Rapoport
NIH - NIAAndrew Singleton