landmark study on genetic etiology of schizophrenia

1.  LANDMARK STUDIES ON GENETIC
ETIOLOGY OF SCHIZOPHRENIA.
Presenter : Dr. Bikram Kafle
3rd year Psychiartry Resident
Department of psychiatry and mental health,IOM

2.  Aetiology – no single cause
 Results from cumulative effects of number of
risk factors.
 Familial-genetic and environmental.
 Diathesis- stress model.

3.  Does it aggregate in families?
 Is it inherited from parent to offspring?
 Which chromosomes carry the gene(s)?
 Which gene(s) are associated with it?
 Which gene variant(s) are associated with it?

4.  Most powerful risk factor- having relative
afflicted with the disorder.
 Lifetime risk of broadly defined schizophrenia
increases from about 1% in the general
population to-
 about 10% in first degree relatives of patient
with schizophrenia
 And to about 50% in those with two parents
with the disorder. (Gottesman 1991)

6.  Family studies locate persons affected with a
particular trait or condition and determine
whether their biological relatives are similarly
affected more often then members of the
general population or the control groups.
 If a condition is found to cluster or run in
families it is said to be familial.

7.  The first genetic family study of
schizophrenia—was carried out by Ernst
Riidin in Kraepelin's clinic before World War I
and was published in 1916.
 Many other studies in different countries, by
Riidin's pupils and others (e.g., Schulz 1932,
Kallmann 1938, and studies reviewed by
Zerbin-R.iidin 1967), confirmed the higher
rate of schizophrenia in the relatives of
samples of schizophrenics.

8.  Ten large studies using more rigorous
diagnostic methodology and normal control
groups were published between 1989-2000.
 Confirmed convincingly that schizophrenia
runs in families.
 The morbidity risk in first-degree relatives of
patients with schizophrenia varied widely
from 1.4 to 6.5 percent (up to 16.2 percent in
offspring) and in control from 0-1.9%.

9.  Are the familial factors genetic?
 If a condition is found to be more common in the
relatives of probands, this could be due to shared
genes or to shared environmental factors.
 These shared environmental factor could be
psychological, infectious, social, or other.
 Therefore, in order to confirm that a disorder is
genetic, other types of studies needed to be
conducted, such as twin and/or adoption studies,
which control for the environmental factors.

10.  Twins who are reared together share the same
environment.
 Monozygotic twins share all their genes, while dizygotic
twins share on average only 50%.
 Twin studies compares the concordance rates in MZ and
DZ twines.
 If one assumes that MZ and DZ twins share their
environments to a roughly equal extent, then a higher
concordance in MZ twins implies that the disorder is
genetic.
 A concordance of less than 100% in MZ twins indicates that
environmental factors are also at play.

11.  Kringlen et al(1968)- probandwise 45% MZ, DZ
15%.
 Pollin et al (1969)- probandwise 43% MZ, DZ 9%.
 Gottesman and Shields (1972)- calculated
average proband wise concordance rate for
broadly defined schizophrenia in MZ twins to be
46% , compared with 14% in DZ twins.
 Fischer et all( 1973)-probandwise 56% MZ, DZ
27%.

12.  Klaning (1996)- probandwise 44% MZ, DZ 11%
 Cannon(1998)-probandwise 46% MZ, DZ 9%
 Cardno(2000)-probandwise 43% MZ, DZ 0%
 These difference reflects that while monozygotic
twins share all their genes, dizygotic share on
average only half.
 The studies shows that the concordance rates
estimates are remarkably constant.
 Although some studies has higher concordance ,
because different diagnostic approaches and
different ascertaintment startegies affect the
concordance rates in DZ and MZ twins.

13.  Identical twins reared apart.
 To avoid effects of more similar MZ
environments.
 Fourteen pairs of MZ twins reared apart of
which 9 were concordant for schizophrenia .
(Gottesman and Shields).

14.  Heritibality: Defined as the fraction of total
phenotypic variance of a quantitative trait that is
caused by genes.
 Calculated from twin studies:
 Varies from 0.0 (no heritability) to 1.0 (strong
heritability); >.7 or .8 suggest strong influence of
heredity on trait.
 High estimates of heritability on the basis of twin
studies suggest that genetic factors play a major role
in the familial transmission of the disease.

15.  It is clear that schizophrenia occurs more frequently
in the relatives of patients, and that MZ concordance
is greater than DZ concordance.
 However these findings could still be explained to
some extent by shared environmental factors. The
similarities of the environments shared by MZ twins
tend to be higher than for DZ twins .
 It is difficult to separate the contribution of such
factors in families because children share both genes
and environment with their parents and sibling.
 Adoption studies : control environmental factors

16.  Offer the opportunity of separating the
effects of familiality from genetics.
 General principle behind adoption studies is
that if there is a genetic component to the
disorder studied, the similarity between
adopted children and their biological parents
should be higher than the similarity between
adopted children and their adoptee parents.

17.  The first adoption study was reported by Leonard Heston in
1966.
 He demonstrated that 5(10.6%) out of 47 children of mothers
with schizophrenia who were adopted away within few days of
their birth, later developed schizophrenia compared with
none out of 50 adoptees with no family history of
schizophrenia.
 Similar findings were reported from the Danish-American
Study of Rosenthal et al(1971) who found that significantly
higher proportion of the adopted away offspring of parents
with schizophrenia were classified as having schizophrenia or
borderline schizophrenia than were control adoptees.
 14 (26.9%) of 52 children of schizophrenic parents developed
schizophrenic spectrum illness.
 12(17.9%) of 67 control adoptees developed a broad spectrum
schizophrenia.

18.  Wender et al (1974), using Denmark adoptees
,studied the grown up children , who by mischance,
had been placed with an adoptive parent who later
developed schizophrenia, and found that they were at
no increased risk of the disorder.
 28 children of normal parents raised by
schizophrenic parents and 69 adopted children of
schizophrenic parents.
 13(18.8%) of 69 children of schizophrenic parents
developed borderline schizophrenia.
 3(10.7%) of 28 children of normal parents , adopted
by future schizophrenics developed borderline
schizophrenia.

19.  Kety et all (1994) ,reported on the same
denmark adoptees.
 Reverse approach was used by the
researches.
 Starting with all adopted people who
developed with schizophrenia , and then
interviewing their biological and adoptive
relatives, as well as biological and adoptive
relatives of unaffected adoptees.

20.  Of 279 biological relatives of adoptees who had
schizophrenia, 14(5%) had chronic schizophrenia,
and other 30(10%) were diagnosed with latent
schizophrenia.
 Of 111 adoptive relatives of adoptes with
schizophrenia, no cases of chronic schizophrenia
were found , and only 2(1.8%) had latent
schizophrenia.
 The study also investigated a total of 351
biological and adoptive relatives of 47 unaffected
adoptees, finding one case of
schizophrenia(0.3%), and 6 cases of latent
schizophrenia(1.7%).

21.  Kendler et all reanalyzed Ketys sample , and found
higher rate of 23.7% of schizophrenia among the first
degree relatives of schizophrenic adoptees, compared
with just 1.2% of such disorders in the adoptive control
relatives.
 Tienari et al (2000,study in Finland), collected data on
all women suffering from schizophrenia whose
children had been adopted. Of 164 such children , 11
had schizophrenia , 1 had schizoaffective disorder, 1
had schizophreniform disorder giving an overall of
schizophrenia spectrum disorder(10.4%).
 The results were compared with 197 control adoptees
of whom only 4 developed schizophrenia(4%).

22.  All adoption studies - similar conclusion.
 Consistently indicate that children of
schizophrenic parents have high risk of
developing schizophrenia even when they are
adopted away very soon after birth.
 This risk is very similar to the risk among
children of schizophrenic parents reported in
family studies suggesting that most of the
familial transmission is genetic , rather than an
effect of upbringing.

23.  We can conclude on the basis of family, twin
and adoption studies evidence, that the
hypothesis of a large genetic contribution to
the aetiology of schizophrenia is true.

24.  Since family , twin ,and adoption studies suggest that
genetic factors are involved in disease causation , to
find specific genes that cause schizophrenia: Linkage
and association studies.
 Linkage: the tendency for alleles at loci that are close
together to be transmitted together as an intact unit
(haplotype).
 Usually involve looking at large families where the
disease affects individuals in several generations.
 The key is to identify a genetic marker that is always
inherited by those family members with the disease
but not by those who do not have the disease.

25.  Linkage studies usually start by identifying genetic
markers, commonly single nucleotide polymorphisms
(SNPs), on a section of a chromosome and then
narrowing the region down until the gene or gene
variant of interest is identified.
 This technique has been used to identify many
disease genes, particularly those that are inherited in
a Mendelian fashion.
 Since 2007, with the availability of array-based
single-nucleotide polymorphism genotyping ,
association studies have also started targeting the
whole genome, with no preference for any genes.

26.  Badner et al (2002) showed the existence of
susceptibility genes on chromosome 8p, 13q,
and 22q.
 Cathryn et al(2005) strongly favored genes on
chromosome 2q . Evidence was also obtained for
linkage to regions on chromosome 1q, 3p, 5q,
6p, 8p, 11q, 14p, 20q, and 22q.
 The meta-analysis of Sullivan (2005)suggested
that linkage analysis is an imprecise tool:
Implausibly large numbers of genes were
implicated and few genes were consistently
identified in more than a small subset of studies.

27.  Conclusion that can be drawn from linkage studies is
that no single gene for schizophrenia exists,
confirming that it is not a single gene disorder.
Several genomic loci have received support from
several studies.
 Two explanations why the studies have produced
such different linkage findings.
 One is that different genes operate in different
populations. Other is that schizophrenia is caused by
the effect of many genes of small effect, so that the
studies had no power to detect the loci.

28.  The inability of linkage studies to clearly
identify linkage signals and the absence of a
clear mode of transmission in the vast
majority of families affected with
schizophrenia indicate that this is not a
simple Mendelian disorder, but a disorder of
complex inheritance.

29.  Despite the inconclusive results produced by
linkage studies, association studies have led to
the identification of the most plausible candidate
genes.
 Positive linkage findings were followed with fine
mapping association studies of genes in linked
chromosomal regions.
 These efforts identified the genes dysbindin
(DTNBP1 ) and neuregulin 1 (NRG1 ), which are so
far the two most consistently confirmed findings.

30.  Evidence that the Gene encoding dystrobrevin-
binding protein 1 (DTNBP1 ), or dysbindin, has a role
in schizophrenia was first reported by Richard E.
Straub and colleagues in 2002, who undertook
association mapping across the linkage region on
chromosome 6p22.3
 Significant association were found between
schizophrenia and several SNPs and multimarker
haplotypes spanning DTNBP1.
 Talbot et all(2004)and colleagues found that the
presynaptic dystrobrevin-independent fraction of
dysbindin is reduced in schizophrenic brain within
certain glutamatergic neurones of the hippocampus.

31.  Neuregulin 1 (NRG1) was implicated in
schizophrenia following a linkage study in an
Icelandic sample.(2002)
 Association analysis across 8p21-22 revealed
highly significant evidence for association
between schizophrenia and a multimarker
haplotype of NRG1 .
 Strong evidence for association with the same
haplotype was subsequently found in a large
sample from Scotland and United Kingdom
sample.

32.  Other candidate genes have been implicated over
the years.
 These include DAOA( D amino acid oxidase
activator)
 G72, COMT (catecholamine O-methyl
transferase), RGS4( regulator for G protein
function) .
 None has received universal replication, so their
status remains uncertain.

33. (Harrison & Owen 2003 The Lancet
361: 417)

34.  Two large GWA studies on schizophrenia have been
published.
 The first one was based on the CATIE study of
antipsychotic response and reported on 738 patients and
733 controls, using Affymetrix 500K arrays, that genotype
approximately 500,000 single nucleotide polymorphisms
(SNPs), (Sullivan et al, 2008)
 Despite a number of promising associations, no SNP
reached genome-wide significance.
 (Donovan et al, 2008). used the same Affymetrix 500K
platform to genotype 479 UK cases and 2937 UK controls,
and followed up the most promising loci in up to 6829
cases and 9897 controls from several populations . The
strongest finding was on chromosome 2 around the
putative zinc finger protein ZNF804a.

35.  Genetics doesn’t completely explain the
disorder
 Diathesis-stress model
 Family, twin and adoption studies favor that
schizophrenia is a genetic disorder.
 Linkage and association studies further help
in identifying candidate genes that is
responsible for pathogenesis.

36.  Kaplan and Sadock’s Comprehensive
Textbook of Psychiatry, 9th edition.
 New Oxford Textbook of Psychiatric 2nd
edition
 A critical review of recent adoption, twin, and
family studies of schizophrenia –Irving I
gottesman.