genetic aspect of schizophrenia, autism and bipolar

1. GENETIC ASPECTS OF SPECIFIC
PSYCHIATRIC DISORDERS
BY
Dr. Gaylord INENA WA INENA
Mmed Psychiatry
SUPERVISOR: Dr. Benedict AKIMANA;Psychiatrist

2. OUTLINE
• INTRODUCTION
• AUTISM SPECTRUM DISORDER
• SCHIZOPHRENIA
• BIPOLAR DISORDERS
• CONCLUSION
• REFERENCES

3. INTRODUCTION
-The human genome sequence is 99.6%
identical in all people.
-However there are certain positions on the DNA
where some people have one nucleotide pair,
while others have another
-Differences at these places make us unique

4. AUTISM SPETRUM DISORDER
• 15% appear to be associated with a known genetic
mutation
• in most cases, its expression is dependent on multiple
genes.
• Family, Twins and Genetic studies have shown evidence

5. FAMILY STUDIES
-Increased rates of autism in siblings of an index
child,
-As high as 50 % in some families with two or
more children with autism spectrum disorder.
-Increased risk( developmental, communication
and social skills) in Sibling,
Even when they do not meet criteria for ASD

6. TWIN STUDIES
Concordance rate of autistic disorder in two large twin
studies:
-36 % in monozygotic pairs / 0 % dizygotic (1st)
-96 % in monozygotic pairs /27% dizygotic (2nd)
 High rates of cognitive impairments, in the non autistic
monozygotic twins with perinatal complications,
--perinatal environmental factors interact with genetic
vulnerability differentially in ASD.

7. GENETIC STUDIES
• There are multiple patterns of genetic transmission.
• Both ,an increase and decrease in certain genetic patterns may be
risk factors for ASD.
• In addition to specific genetic factors, gender plays a strong role in
the expression of autism spectrum disorder.
• 2 biological systems influence in ASD
-Elevated platelet serotonin (5-HT), and
- Disrupt of plasticity mechanisms of MTOR(mammalian target of
rapamycin–linked synaptic).

8. Genetic studies….
The most common inherited disorders is :
1.Fragile X syndrome
- An X-linked recessive disorder that is
- Present in 2 to 3 percent of individuals with ASD .
- Exhibits a nucleotide repeat in the 5’untranslated
region of the FMNR1 gene,
- Resulting in symptoms of ASD.
•

9. Genetic studies…
• Children who have it exhibit:
-Intellectual disability,
-Gross and fine motor impairments,
-An unusual facies,
-Macroorchidism, and
-Significantly diminished expressive language
ability.

10. GENETIC…
2.Tuberous sclerosis,
characterized by:
-Multiple benign tumors,
-Inherited by autosomal dominant transmission,
- Found with greater frequency among children with
ASD,
- Up to 2 percent of children with ASD also have
tuberous sclerosis.

11. GENETIC…
• Screened the DNA of more than 150 pairs of
siblings with ASD found :
-Two regions on chromosomes 2 and7
-Containing genes contributing to ASDutism .
- Additional genes hypothesized on
chromosomes 16 and 17

12. BIOMARKERS IN ASD
ASD
• is associated with several biomarkers,
• potentially resulting from interactions of genes
and environmental factors,
• which then influence neuronal function, dendrite
development, and
• contribute to altered neuronal information
processing.

13. Biomarkers…
• Several biomarkers:
-Of abnormal signaling in the 5-HT system,
- The mTOR-linked synaptic plasticity
mechanisms, and
- alterations of the γ-aminobutyric acid (GABA)
inhibitory system

14. BIOMARKERS…
First biomarker identified in ASD was :
-Elevated serotonin in whole blood,
-Almost exclusively in the platelets.
-Platelets acquire 5-HT through the process of SERT
(serotonin transporter),
-Known to be hereditary, as they pass through the
intestinal circulation.

15. BIOMARKERS…
• The genes that mediate SERT (SLC64A), and the
5-HT receptor 5-HT2A gene (HTR2A)
-Are known to be more heritable than ASD
-Encode the same protein in the platelets and in the
brain.
• Because 5-HT is known to be involved in brain
development
- Possible that the changes in 5-HT regulation
- may lead to alterations in neuronal migration and
growth in the brain.

16. BIPOLAR AFFECTIVE DISODER
Genetic Factors
-Numerous family, adoption, and twin studies
have long documented the heritability of
mood disorders.
-Recently, the primary focus of genetic studies
has been to identify specific susceptibility
genes using molecular genetic methods

17. Family Studies.
Family data indicate :
-If one parent has a mood disorder, a child will
have a risk of between 10 and 25 % .
-If both parents are affected, this risk roughly
doubles.
- The more members of the family who are
affected, the greater the risk is to a child.

18. Family studies…
• First-degree relatives rather than more distant
relatives.
• A family history of bipolar disorder conveys a
greater risk for mood disorders in general and,
specifically, a
much greater risk for bipolar disorder.
• Unipolar disorder is typically the most common
form
of mood disorder in families of bipolar probands.

19. Family studies…
• This familial overlap suggests some degree of
common genetic underpinnings between
these two forms of mood disorder.
• The presence of more severe illness in the
family also conveys a greater risk (Fig.)

20. Family studies…
• Many different models of genetic transmission
• have been considered and tested
• to see if they would explain the transmission of
mood disorders.
• Some of the more prominent models:
. In Mendelian or single major locus transmission,
one gene
transmits the illness.
.

22. -In polygenic quantitative trait (QTL) model,
multiple genes add together
To contribute to a quantitative trait.
-In this figure, the X axis represents the number
of polygenes that a given individual is
carrying, as well as the value of the
resulting quantitative trait

23. Adoption Studies
• provide an alternative approach to separating genetic
and environmental factors in familial transmission.
• Only a limited number of such studies have been
reported, and their results have been mixed.
• One large study found a threefold increase in the rate
of bipolar disorder and a twofold increase in unipolar
disorder in the biological relatives of bipolar probands.

24. Adoption Studies…
• Similarly, in a Danish sample, a threefold
increase in the rate of unipolar disorder and a
sixfold increase in the rate of completed
suicide in the biological relatives of affectively
ill probands were reported.
• Other studies, however, have been less
convincing and have found no difference in
the rates of mood disorders

25. Twin studies
provide the most powerful approach
to separating genetic from environmental factors, or “nature”
from “nurture.”
The twin data provide compelling evidence that:
- Genes explain only 50 to 70 percent of the etiology of
mood disorders.
- Environment or other non heritable factors must explain
the remainder.
- Therefore, it is a predisposition or susceptibility to disease
that is inherited.
-

26. Twins studies
- Considering unipolar and bipolar disorders
together,
- These studies find a concordance rate for
mood disorder in the monozygotic (MZ) twins
of 70 to 90 percent compared with the same-
sex dizygotic (DZ) twins of 16 to 35 percent
- This is the most compelling data for the role of
genetic factors in mood disorders

27. Linkage Studies
• DNA markers are segments of DNA of known
chromosomal location,
which are highly variable among individuals.
• They are used to track the segregation of specific
chromosomal regions within families affected
with a disorder.
• When a marker is identified with disease in
families, the disease is said to be genetically
linked (Table below)
•

28. Linkage studies…
• Chromosomes 18q and 22q are the two regions
with strongest evidence for linkage to bipolar
disorder.
• Several linkage studies have found evidence for
the involvement of specific genes in clinical
subtypes.
Eg. the linkage evidence on 18q has been shown to
be derived largely from bipolar II–bipolar II sibling
pairs and from families in which the probands
had panic symptoms

30. Linkage studies…
• Gene-mapping studies of unipolar depression have
found:
- very strong evidence of linkage to the locus for cAMP
response element-binding protein (CREB1) on
chromosome 2.
- Eighteen other genomic regions were found to be
linked; some of these displayed interactions with the
CREB1 locus.
- Another study has reported evidence for a gene–
environment interaction in the development of major
depression

31. Linkage studies…
• Subjects who underwent adverse life events were
shown, in general, to be at an increased risk for
depression.
• Of such subjects, however, those with a variant in
the serotonin transporter gene showed the
greatest increase in risk.
• This is one of the first reports of a speciϧc gene–
environment interaction in a psychiatric disorder.

32. SCHIZOPHRENIA…
• The modes of genetic transmission in
schizophrenia are unknown,
• Several genes appear to make a contribution to
schizophrenia vulnerability.
• Linkage and association genetic studies have
provided strong evidence for nine linkage sites:
1q, 5q,
6p, 6q, 8p, 10p, 13q, 15q, and 22q.

33. SCHIZOPHRENIA…
• Further analyses of these chromosomal sites
have led to the identification of specific candidate
genes, and
• The best current candidates are α-7 nicotinic
receptor, DISC 1, GRM 3, COMT, NRG 1, RGS 4,
and G 72.
• Recently, mutations of the genes dystrobrevin
(DTNBP1) and neureglin 1 have been found to be
associated with negative features of
schizophrenia.

34. SCHIZOPHRENIA
• There is a genetic contribution to some, perhaps
all, forms of schizophrenia,
• high proportion of the variance in liability to
schizophrenia is due to additive genetic effects.
E.g. schizophrenia and schizophrenia-related
disorders (e.g., schizotypal personality disorder)
occur at an increased rate among the biological
relatives of patients with schizophrenia.

35. SCHIZOPHRENIA…
• The likelihood of a person having
schizophrenia is correlated with the closeness
of the relationship to an affected relative (e.g.,
first- or second-degree relative).
• In the case of monozygotic twins ,50 %
concordance rate for schizophrenia

36. SCHIZOPHRENIA…
• . This rate is four to five times the concordance
rate in dizygotic twins or the rate of occurrence
found in other first-degree relatives (i.e., siblings,
parents, or offspring).
• The role of genetic factors is further reflected
in the drop-off in the occurrence of schizophrenia
among second- and third-degree relatives,
in whom one would hypothesize a decreased
genetic loading

37. SCHIZOPHRENIA…
• The finding of a higher rate of schizophrenia
among the biological relatives of an adopted-
away person who develops schizophrenia,
compared with the adoptive, non biological
relatives who rear the patient, provides
further support to the genetic contribution in
the etiology of schizophrenia.
.

38. SCHIZOPHRENIA
• Monozygotic twin data clearly demonstrate :
The fact that individuals who are genetically
vulnerable to schizophrenia do not inevitably
develop schizophrenia; other factors (e.g.,
environment) must be involved in determining
a schizophrenia outcome

39. SCHIZOPHRENIA…
-Some data indicate that the age of the father
has a correlation with the development of
schizophrenia.
- (those born from fathers older than the age of
60 years were vulnerable.)
- Presumably, spermatogenesis in older men is
subject to greater epigenetic damage than in
younger men

40. CONCLUSION
• Genes operate at a very basic cellular level.
• Genes do not code for mental illness or for
symptoms of mental illness.
• Genes do not respect the boundaries of
schizophrenia, schizoaffective, bipolar disorder or
Alzheimer’s disease.
• Genes do not seem to validate the DSM.
• For instance neuregulin (positive in 15 studies
world wide) is present in schizophrenia, bipolar
disorder and Alzheimer’s disease

41. REFERENCES
• From Sadock BJ, Sadock VA, Ruiz P. Kaplan
& Sadock’s Comprehensive Textbook of
Psychiatry. 9th ed. Philadelphia: Lippincott
Williams & Wilkins, 2009.

42. MANY THANKS
Patrick Archange and Theonor Michaelange