Genetics in schizophrenia

GENETICS IN SCHIZOPHRENIA 6/1/2012 2

 Rationale for genetic study in Schizophrenia
 Common definitions
 Sub-fields in genetics
 Family studies
 Twin studies
 Adoption studies
 Linkage studies
 Association studies and GWAS
 Chromosomal aberrations and CNVs
 Challenges and future of genetics in schizophrenia
 Take home message


 SCZ- schizophrenia
 MZ- monozygotic
 DZ- dizygotic
 GWAS- Genome-wide Association Studies
 LD- Linkage Disequilibrium
 ISC- International Schizophrenia Consortium
 MGS- Molecular Genetics of Schizophrenia
 SGENE- Schizophrenia Genetics Consortium


 Overall, psychiatric diseases are
› First-rank public health problems
› Cause enormous morbidity, mortality and
personal/societal cost
› Mostly idiopathic
› Despite considerable research, little known for
certain about the disease etiology
 Genetic knowledge of SCZ
› Can give a definite biological basis for
distinguishing affected from non-affected
(Sullivan 2010)
 Can guide for newer treatments


 Concordance: proportion of co-twins who
are also affected or the proportion of twin
pairs where both twins are affected
 Heritability: proportion of the variance of a
phenotype(disease, trait) that is due to
genes, estimated from risks to twins and
other relatives
 Mendelian disease: caused by a (usually
rare) change(mutation) in DNA sequence
on one(dominant) or both(recessive) of an
individual’s pair of chromosomes

 Complex disease: caused by an interaction of
multiple genetic and/or environmental factors
 Linkage disequilibrium(LD): nonrandom
association of alleles at the adjacent loci
› A variant that is highly correlated with a truly
causal variant will show a similar statistical
association to phenotype if the LD is widespread,
many fewer markers will need to be assayed
(Psychiatric GWAS consortium coordinating
committee 2009)


 SNP “snips”( Single nucleotide
polymorphism): specific position(among
3.2billion in the genome) where
chromosomes carry different nucleic acids
 Common SNPs: ≥5% frequency ~10million in
the genome- targets of the GWAS
 Rare SNPs: <1% frequency
 Copy number variant(CNV): chromosomal
segment where DNA has been deleted or
duplicated


 Genomewide Association Study(GWAS): a
systematic search for the common SNPs
that influence a disease or trait, using a
genomewide SNP array for typing a cohort
of individuals
 Common-disease common-variant
hypothesis: many different common SNPs
have small effects on each disease
 Pleiotropy: The single gene controlling or
influencing multiple (and possibly
unrelated) phenotypic traits.

 Biochemical genetics: biochemical
reactions by which genetic determinants
are replicated and produce their effects
 Developmental genetics: how the
expression of normal genes controls
growth and developmental processes
 Molecular genetics: structure and
functioning of genes at molecular level.
 Cytogenetics: chromosomes

 Population genetics: mathematical
properties of genetic transmission in families
and populations- evolutionary genetics,
genetic demography, quantitative
genetics, genetic epidemiology
 Quantitative genetics: goal is to partition
the observed variation of phenotypes into
genetic and environmental components
 Genetic epidemiology: understanding the
causes, distribution and control of disease in
groups of relatives and the multifactorial
causes of disease in populations

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GENETICS IN SCHIZOPHRENIA 6/1/2012

 FAMILY STUDIES
 TWIN STUDIES
 ADOPTION STUDIES
 LINKAGE STUDIES
 ASSOCIATION STUDIES
 GENOMEWIDE ASSOCIATION STUDIES
 CHROMOSOMAL ABERRATIONS AND
COPY NUMBER VARIANTS

14


 Study of families of probands to see if the
relatives of the probands have increased
risk of developing the disease
 Ernst Rudin(1916): first systematic family
study
 Other prominent researchers: Edith
Zerbin-Rudin, Irving I. Gottesman, Franz
Kallmann, Manfred Bleuler


 Data showed the familial basis of
schizophrenia with increased risk of
developing schizophrenia in the relatives
of schizophrenic patients
 Bezugsziffer: an age-adjusted size of the
sample which takes into account the
fact that younger persons have not
passed through the full period of risk-
traditionally 15-39yrs
 Average lifetime prevalence risk of 10%
in siblings and children

 General population:  Siblings(parents well):
1% 9.6%
 First cousins,  Siblings(one parent
uncles/aunts: 2.4% schizophrenic): 16.7%
 Nephew/nieces: 3%  Children: 12.8%
 Grandchildren: 3.7%  Children with both
 Half siblings: 4.2% parents
 Parents: 5.6%
schizophrenic: 46.3%
 All siblings: 10.1%
(Kirov G 2009)


 Lower risk among parents explained by
the reduced reproductive fitness
associated with schizophrenia and the
possibility of de novo mutations causing
the illness in the offspring*
 Earlier studies questioned on the
methodological grounds: no control
groups, diagnoses not made blind, no
structured interviews or operationalized
diagnostic criteria used

GENETICS IN SCHIZOPHRENIA 20
((Kirov G,2009)6/1/2012

 No major difference in the findings of newer
studies as compared to that of older ones
 Significant difference for parents(5.6% in
older ones vs. 2.3% in newer) could be due
to application of more stringent diagnostic
criteria*
 Confirmed the higher risk of SCZ in the
relatives of the probands but did not
delineate the role of shared genetic or
environmental factors in this difference

22


 Compare the concordance rates in
Monozygotic(MZ) and Dizygotic(DZ) twins
 MZ twins share all their genes while DZ twins
share on average 50% of their genes
 Principle: assuming twins share common
environment,
› higher concordance in MZ twins than in DZ
implies genetic origin
› Concordance of less than 100% in MZ twins
indicate the role of environment

 Allow for the estimation of:
› Proportion of variance due to shared
environmental factors(c2)-
› Proportion of variance due to non-shared
environmental effects(e2)
[shared environment- the effects of those
non-genetic factors that make both
twins more likely to have similar
phenotypes]
[non-shared environment- the effects of
factors that make twins different]

 Pairwise concordance: simply the number of
concordant pairs divided by the total number
of pairs
 Probandwise concordance: each of the
concordant twin is counted i.e. the pair is
counted twice and is ascertained by
› number of affected co-twins/ the number of
probands
› Gives the risk for the twin of a person suffering from
SCZ to become ill him/her-self
› Preferred by geneticists- technically more correct
and directly comparable to population risks reported
in family studies


(Kirov G,2009)

 Probandwise concordance in MZ twins:
25%(n=8)(Essen-Moller,1970)
78%(n=245)(Kallmann,1946)
 Probandwise concordance in same-sex
DZ twins: 0%(n=50)(Cardno,1998)- 28%
(n=25)(Franzek and Beckmann,1998)
 Heritability: 41%- 90%- very similar
estimates with both the
methodologically superior and inferior
studies(Sullivan)

 Meta-analyses of heritability:
› Sullivan- 81% (Sullivan, 2007)
› Cardno and Gottesmann- 88% (Cardno,
2000)
 High agreement between studies
conducted in different countries over
nearly a century
 Calculation based on assumptions:
› Polygenic multifactorial threshold model
› Similar risk of SCZ in twins as in general
population
› DZ and MZ twins share similar environment

 Identical twins reared apart: theoretically
nullifies the effects of shared environment
› 9/14( Gottesmann and Shields)=64%
 Possible explanations for the discordance in
MZ twins:
› Affected co-twin suffers from an environmentally
determined form of the disorder
› Both twins inherited the same genetic liability but
only expressed in the affected twin
 Explained by the study of risk in the offspring
of discordant SCZ twins

 First study
› 11 SCZ twins, 47 offspring with 6 developing SCZ
16.8%
› 6 unaffected twins, 24 offspring with 4 developing
SCZ 17.4%
 Second study
› 28 offspring of SCZ twins with 3 developing SCZ
10.7%
› 45 offspring of unaffected twins with 1 developing
SCZ 2.2%
 Combined:
› risk among offspring of SCZ twins, 9/75=12%
› Risk among offspring of unaffected, 5/69= 7.2%
(P=0.38)no significant difference similar morbidity
risk consistent with unexpressed risk (Kirov , 2009)

31


 Allow dissection of genetic from
environmental contributions in ways that
twin studies cannot
 Principle:
› if there is a genetic component to the disorder,
the similarity between the adopted children and
their biological parents should be higher than
the similarity between adopted children and
their adoptive parents
› Adoption itself does not increase the risk for
developing SCZ among adopted children


 Leonard Heston, 1966:
› 47 adopted children of mothers suffering from SCZ
and other psychoses, separated within 3days of birth-
by age 36, 5 developed SCZ(10.6%)
› None out of 50 children in the control group had SCZ
 David Rosenthal, 1971:
› Studied 5500 adoptees
› 14/52(26.9%) children of SCZ parents had SCZ-
spectrum d/o
› 12/67 control(17.9%) had illness of similar spectrum
(Kirov, 2009)


 M. W. Higgins, 1976:
› 50 children of SCZ mothers
› 4/23(17.9%) children reared by SCZ mothers
had SCZ
› Of 25 children adopted away, 4(16%) SCZ
 Seymour S. Kety and colleagues, 1994
› 14/279(5%) biological relatives of SCZ
adoptees had chronic SCZ
› None out of 111 adoptive relatives had SCZ
› 1/351(0.3%) biological + adoptive relatives of
unaffected adoptees had SCZ

 Pekka Tienari, 2000:
› 164 adopted children of mothers suffering
from SCZ or paranoid d/o
 SCZ- 11(6.7%)
 Schizoaffective- 1(0.6%)
 Schizotypal personality d/o- 4(2.4%)
 Overall narrow spectrum SCZ d/o- 10.4%
› 197 control adoptees
 SCZ - 4(2%)


 CONCLUSION:
› Overall at least 10% risk of developing SCZ
and other narrow-spectrum SCZ disorders in
adopted away children of SCZ parents
› Risk similar to that in offspring in family studies
 genetic basis of transmission of SCZ


37


 A statistical procedure by which
pedigree data are examined to
determine whether a disease phenotype
is cosegregating with a genetic marker
of known chromosomal location
 Demonstration of linkage between a
putative disease susceptibility locus and
one or more genetic markers determines
in which chromosomal region the
disease locus lies

 Use of large number of small families
containing individuals who are definitely
affected rather than large, multigenerational
pedigrees
 At least 27 whole genome studies that
analyzed between 1 to 294 pedigree
containing between 32 to 669 patients of SCZ
 J. A. Badner and E.S. Gershon- susceptibility
genes on chromosomes
› 8p, 13q and 22q
 Cathryn M. Lewis and colleagues-
› Strong evidence for 2q
› 1q, 3p, 5p, 6p, 8p, 11q, 14q, 20q and 22q

 Meta-analysis by Sullivan-
› Only 42%, 35%, 14%, 6% and 3% of all known
genes were implicated by zero, one, two, three
and four linkage studies imprecise tool
 Possible explanations for the varied linkage
findings:
› Different genes operate in different populations
› SCZ is caused by the effect of many genes of
small effect, so studies had no power to detect
the loci


 Hypotheses regarding genetic
background of common diseases
including SCZ:
› Common disease/common variant
hypothesis:
 Common diseases caused by common
variants
 Joint action of several common genetic
variants, each has a small effect on disease
susceptibility, together with environmental
factors
 Could range into thousands

 Multiple rare variants in different genes,
which have low population frequencies,
operate in different individuals:
› lack of families with clear cut Mendelian
Inheritance
› Inability of linkage studies to find any
causative mutation
› Mathematical modeling is inconsistent with
single gene of large effect
› A small number of cases of SCZ could be
due to rare chromosomal aberrations with
high penetrance

44


 Principle:
› association studies implicate a specific gene
by identifying a correlation between a
disease and alleles at a specific genetic
locus
› Compares the frequency of marker
genotypes in cases with an appropriate
control group
› SNPs are the most common source of
genetic measurement in association studies

 Dystrobrevin-binding protein1(DTNBP1)/
dysbindin
› First reported by Richard E. Straub and
colleagues in 2002
› On chromosome 6p22.3
› Konrad Talbot(2004)- presynaptic
dystrobrevin-independent fraction reduced
in SCZ brain within certain glutamatergic
neurones in the hippocampus  associated
with increased expression of vesicular
glutamate transporter type 1alteration in
presynaptic glutamate function

 DTNBP1…
› Significant associations found between SCZ
and several SNPs and multimarker
haplotypes spanning DTNBP1
› Support from other large studies as well- at
least 10 studies
› Some studies showing no association
› Inconsistencies indicative of presence of
multiple susceptibility and protective alleles


 Neuregulin 1(NRG1)
› Encodes multiple proteins with diverse range of
functions in the brain
 Cell-cell signaling
 ErbB receptor interactions
 Axon guidance
 Synaptogenesis
 Glial differentiation
 Myelination
 Neurotransmission
› Located on 8p21-22


 NRG1…
› First implicated from linkage study in
Icelandic sample
› Further positive findings supported by studies
from UK, Irish, Chinese, Bulgarian and South
African samples
› Only 3 other studies replicating the specific
haplotype  differences in linkage
disequilibrium


 Other genes:
› Catechol-O-Methyltransferase (COMT)
› Proline Dehydrogenase (PRODH)
› Regulator of G-protein signaling4 (RGS4)
› D-Amino-acid oxidase (DAO)
› D-Amino-acid oxidase activator (DAOA)
› G72/G30
› CAPON
› AKT1

51


 Common variant SNPs:
› minor allele frequency of SNPs>0.05
 The effect sizes of the associations likely
to be very small  hundreds and even
thousands of genes might contribute
small effects to the pathogenesis of SCZ


 RELN gene:
› Relin protein- a serine protease important in
corticogenesis (Hong et al, 2000)
› Implicated in neurotransmitter-related GSK3β
signaling and regulation of NMDA receptor
activation (Herz, 2006)
› Polymorphism in RELN associated with
neurocognitive endophenotypes of
SCZ(working memory and executive
functioning) (Wedenoja, 2008)


 Genome-pooling based study
› rs11064768 in intron 1 of CCDC60 on
12q24.23
› rs11782269 on 8p23.1
› RBP1 on 3q23- implicated in SCZ
pathogenesis
› Not replicated in other studies and no
genome-wide significance
 Suggestive of neurodevelopmental
hypothesis of SCZ (Keshavan et al 2004)

 Zinc finger protein 804A(ZNF804A)
› Located on 2q32.1
› Putative transcription factor
› Shown to be associated with disturbed
connectivity between the dorsolateral
prefrontal cortex(DLPFC) & the
hippocampus; between rt. and lt.
hemisphere (Esslinger et al 2009)
› Strong association with SCZ and BPAD
› Supported by replication in other large
studies as well

 Major histocompatibility complex(MHC):
› Significant association shown by the meta-
analysis of the three major GWAS (ISC, MGS, and
SGENE) at the MHC region on chromosome 6
› Genes in the MHC region have different
functions immune function predominate
› Histones regulate DNA transcription by
chromatin modification and have role as
antimicrobial agent genetic variation in
histones might underlie differential placental
susceptibility to infection susceptibility to SCZ*
(Gejman et al 2010)

 MHC…
› Danish study registry  increased risk of
autoimmune diseases for schizophrenics and a
history of any autoimmune d/o(n=29) associated
with 45% increase in the risk for SCZ (Eaton et al,
2006)
 Neurogranin(NRGN):
› On chromosome 11
› Encodes a postsynaptic protein kinase substrate
that binds calmodulin, mediating NMDA
receptor signaling  important for learning &
memory, relevant to proposed glutamate
pathophysiology of SCZ(Wang et al, 2008)


 Transcription factor 4 (TCF4):
› On chromosome 18
› Neuronal transcriptional factor essential for
brain development, esp. neurogenesis
› Mutations cause Pitt-Hopkins syndrome, a
neuro-developmental d/o


 International Schizophrenia Consortium
( ISC) conclusion:
› Thousands of common polygenic variants
with very small individual effects explain
about 1/3rd of the total variation in genetic
liability to SCZ (Purcell et al, 2009)
› The remaining heritability is still missing even
after the well powered GWAS studies


(Gejman,2010)


61


 CNVs:
› are stretches of genomic deletions &
duplications ranging from 1kb to several Mb
› Likely to have larger phenotypic effects than
SNPs
› Only rare(<1%) and large(>100kb) CNVs have
been implicated in SCZ
› Chromosome 22q11.21 deletion syndrome
 Velocardiofacial syndrome
 Increased risk for SCZ >30% carriers develop
psychosis,80% of which as SCZ
 Largest known individual risk factor for SCZ second
only to having an identical twin with SCZ

 CNV:
› 2p16.3 Neurexin1(NRXN1) deletion
 NRXN presynaptic cell adhesion molecule
 Interact with post synaptic cell adhesion
molecules including neuroligins
 Believed to play important role in release of
neurotransmitter from presynaptic vesicles and
together with neuroligins involved in synapse
formation and use-dependent validation of
neural circuits
 Partial overlapping observed in mentally
retarded and autistic patients

 Disrupted In Schizophrenia(DISC1):
› Balanced chromosomal translocation
in(1,11) (q42;q14.3)
› Disrupt two genes in chromosome1 : DISC1 &
DISC2
› Strong evidence of linkage to- SCZ, BPAD
and recurrent depression


 DISC1…:
› May contribute to SCZ by affecting neuronal
functions dependent on intact cytoskeletal
regulation such as
 Neuronal migration
 Neurite architecture
 Intracellular transport


 CNV:
› 15q13.1 duplication
 Duplicated interval in the proband contains 3
genes of which APBA2 appears most likely
 APBA2 interacts with NRXN1
› 1q21.1 deletion
› 15q13.2 deletion
› 15q13.3 deletion
 Also found in pts. With mental retardation and
seizures
› 16p11.2 duplication

 Many of the genes positive for SCZ also positive
for BPAD and vice versa
 With BPAD
› DISC1
› NRG1
› RELN
› ANK3
 With autism
› Neurexin 1
 Could have implication for diagnostis of SCZ
and also lead to newer etiological and
pathophysiological explanations of the
psychiatric disorders

(Stahl SM, 208)

 Standardization of the phenotypes:
› Syndromal diagnosis
› Broad variations
 The effect size associated with common
variant is very low and the number of total
susceptibility variants may be in the order of
thousands requiring upto 100,000 cases and
controls for replicating the findings
› To achieve such sample sizes with detailed and
consistent phenotype measurement is a challenge
 Combining all diseases of a spectrum e.g.
psychosis, broadly large sample size and also
detect genes that overlap

 Narrow the phenotype more
homogenous sub-group smaller number
of genes of greater effect sizes
 Use of endophenotypes(Gould 2006):
› Disease associated phenotypes that are
heritable, state independent, cosegregate with
families and also found in unaffected family
members
› E.g.
 Abnormal eye movement while tracking a moving
object in screen
 Neurocognitive deficits- COMT & RELN
 Structural imaging phenotypes
› Creates phenotypically more homogenous
group

 Consideration of the effect of
environmental factors such as maternal
infections, and drug use
 Consideration of epigenetic mechanisms
 Use of high-throughput whole-genome
sequencing:
› Has potential to detect virtually all SNPs,
CNVs and epigenetic modifications*
› Will provide comprehensive information of
an individual at the DNA level
› Cost concern
GENETICS IN SCHIZOPHRENIA 71
6/1/2012

 More accurate study of the target organ
in SCZ research(brain) can lead to more
objective and reliable associations with
the genetic variants


73


 Though Psychiatric diseases, including SCZ are quite
common and the burden of illness quite high still little
is known for certain about the disease etiology
 Genetic study of SCZ can provide us with the
etiological basis and also guide us into newer and
better treatment
 With the clustering of SCZ in families, family studies
showed
› the average morbidity risk of 10% in the siblings of
probands,
› confirmed the higher risk of SCZ in the relatives of the
probands but did not delineate the role of shared genetic
or environmental factors in this difference

 Twin studies:
› Compare the concordance rates in
Monozygotic(MZ) and Dizygotic(DZ) twins
› Probandwise concordance in Monozygotic
twins in the range of 25-78%; same sex
dizygotic twins 0=28%; and heritability 81-
88%
› Higher concordance in the MZ twins than
that in dizygotic  genetic basis but <100%
concordance in MZ  possible role of
environmental factors

 Adoption studies:
› Allow dissection of genetic from
environmental contributions
› Overall at least 10% risk of developing SCZ
and other narrow-spectrum SCZ disorders in
adopted away children of SCZ parents

 Linkage studies:
› 8p, 13q and 22q, 2q, 1q, 3p, 5p, 6p, 11q, 14q,
20q
› problem with non-replication across studies
s/o SCZ is caused by the effect of many
genes of small effect, so studies had no
power to detect the common loci

 Common disease/common variant
hypothesis:
› Common diseases caused by joint action of
several common variants each having a
small effect on disease susceptibility
 Multiple rare variants in different genes
with large effect, which have low
population frequencies, operate in
different individuals to cause SCZ

 Association studies:
› Compares the frequency of marker
genotypes in cases with an appropriate
control group
› Dystrobrevin-binding protein1(DTNBP1)/
dysbindin, On 6p22.3
› Neuregulin 1(NRG1) on 8p21-22
› COMT, PRODH, RGS4, DAO, DAOA, G72/G30,
CAPON, AKT1

 GWAS:
› Thousands of common polygenic variants with
very small individual effects explain about 1/3rd
of the total variation in genetic liability to SCZ
(Purcell et al, 2009)
› The remaining heritability is still missing even after
the well powered GWAS studies
› RELN gene, 12q24.23, 8p23.1, 3q23, Zinc finger
protein 804A(ZNF804A) on 2q32.1, Major
histocompatibility complex(MHC) on
chromosome 6, Transcription factor 4 (TCF4) on
chromosome 18

 CHROMOSOMAL ABERRATIONS/COPY
NUMBER VARIANTS:
› Likely to have larger phenotypic effects than
SNPs
› Chromosome 22q11.21 deletion syndrome,
2p16.3 Neurexin1(NRXN1) deletion, Disrupted In
Schizophrenia(DISC1), 15q13.1
duplication,1q21.1 deletion, 15q13.2 deletion,
15q13.3 deletion, 16p11.2 duplication
 Overlapping genes with BPAD: DISC1,
NRG1, RELN, ANK3 lead to newer
etiological and pathophysiological
explanations of the psychiatric disorders

 Strong genetic basis of SCZ proven from
age-old family studies to the ultra modern
GWAS
 Specific genes and loci still not definitely
established though showing high degrees
of association
 Problem arising out of multiple factors:
 the lack of operationalized phenotypes
 The presence of large number of common
variants of small effects leading to problems of
replication across studies
 Cost, manpower and expertise inadequacy


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