Schizophrenia has a strong genetic component based on family and twin studies. While no single gene causes schizophrenia, genome-wide studies have implicated several genomic regions and candidate genes may play a role. Environmental factors like stress, abuse, and viruses during development can also influence risk. The dopamine and neurodevelopmental hypotheses propose that imbalances in brain chemistry like dopamine, or abnormalities in brain development, may underlie the disorder. Continued research on genetics, the brain, and environment aims to further elucidate the causes of schizophrenia.

1. Schizophrenia
and
Genetics
Narjes Khatoon shabani sadr
Provided for: behavioral genetics-doctor
Forughmand

3. Introduction

4. • The symptoms of schizophrenia can be categorized
into three wide-ranging groups.
1. Positive symptoms
2. Negative symptoms
3. Cognitive symptoms
Symptoms

5. Symptoms
• Positive symptoms include: hallucinations
(visual and auditory), delusions, and racing
thoughts.
• Negative symptoms include: apathy, lack of
emotion, and poor social functioning.
• Cognitive symptoms include: disorganized
thoughts, difficulty concentrating or
completing tasks, and memory problems.

6. Positive and Negative Symptoms
Negative Positive
A logia (abnormal speech) Hallucinations
Lack of interest in life Delusions
Poor in making decisions Bizarre behavior
Languages impairment Unusual thoughts
Social isolation Disorder of movement

8. • No one knows the exact causes of Schizophrenia, but
multiple possible factors have been discovered.
• These factors include:
1. Genetics
2. Brain chemical imbalance
3. Environmental factors
4. Family history
Causes

9. Etiology of Schizophrenia
• The etiology(causes) and pathogenesis of
schizophrenia is not known
• It is accepted, that schizophrenia is „the
group of schizophrenias“ which origin is
multifactorial:
– internal factors : genetic, inborn, biochemical
– external factors : trauma, infection of CNS,
stress

11. Genetic predisposition
Neurodevelopmental abnormalities and target features
Further brain dysfunction and schizophrenia
Neurodegeneration and schizophrenia
Etiologic pathway
Early environmental insults
Later environmental insults
psychosis

12. Affects 1 %1 % of the general population.
8% in siblings of affected subjects.
12% in offsprings of one affected parent.
40% in offsprings of two affected parents.
47% in subjects of affected monozygotic twins.
Epidemiology

14. Genetics of Scizophrenia

15. What is known about the inheritance pattern of
schizophrenia?
• Although results from family, twin, and adoption studies provide
overwhelming evidence that genetic factors play a part in the cause of
schizophrenia, the exact mechanisms of genetic transmission remain
unidentified.
• Despite the genetic and phenotypic complexity of schizophrenia, much
progress has been made.
• Research has largely excluded the possibility that genes of major effect
exist; linkage analysis has provided independently replicated evidence for
genes of moderate effect on several chromosomal regions.
• Association studies suggest that alleles of at least two genes, those
encoding D3 and 5HT 2A, confer a small rise in susceptibility to
schizophrenia, and there are convergent findings from several different
lines of research implicating regions such as 22q11, although no specific
causative genes for schizophrenia have been definitively identified yet.

16. What genetic testing could you offer this
couple?
• Predictive genetic testing is unlikely to be useful in the
near future except for some rare pedigrees if a single
major locus is identified.
• One area where genetic testing may be more helpful,
however, is schizophrenia associated with VCFS.
• In most cases, the deletion of 22q11 occurs as a de novo
mutation, but in 10% of those affected, it is inherited from
a parent, who may have a mild presentation of the
syndrome .
• In such cases, parents could be tested for the deletion,
and, if confirmed, testing could be offered to siblings,
especially if other clinical features are present.

17. Twin, adoption and family studies

18. Twin, adoption and family studies

20. family studies
• As can be seen from the graph below, schizophrenia definitely has a very
significant genetic component.
• Those who have a third degree relative with schizophrenia are twice as
likely to develop schizophrenia as those in the general population.
• Those with a second degree relative have a several-fold higher incidence of
schizophrenia than the general population, and first degree relatives have
an incidence of schizophrenia an order of magnitude higher than the
general populace.
• Following are two images that summarize the average risks for developing
schizophrenia for different groups of people.
• (The statistics in the two images vary slightly due to inclusion of different
study data).

21. family studies

22. family studies

23. Risk of Developing Schizophrenia (in percents) from
SCHIZOPHRENIA GENESIS

24. family studies

25. Genome-wide studies

26. Genome-wide studies

28. new findings promise new insights

29. If we were to summarize all of these data on an ideogram of the human
genome, they might look like this; to the right of the chromosome is an "S" for
schizophrenia susceptibility, a "B" for bipolar, and an asterisk (*) where both
types of disorders are mapped to the same location.

30. Candidate gene studies: gene studied

31. Candidate gene studies: gene studied

32. Brain-derived neurotrophic(BDNF) gene

33. Brain-derived neurotrophic(BDNF) gene

34. Brain-derived neurotrophic(BDNF) gene

35. Brain-derived neurotrophic(BDNF) gene

36. Brain-derived neurotrophic(BDNF) gene

37. Brain-derived neurotrophic(BDNF) gene

38. Epidermal growth factor(EGF)gene

39. Epidermal growth factor(EGF)gene

40. Epidermal growth factor(EGF)gene

41. Epidermal growth factor(EGF)gene

42. NOTCH4 gene

43. NOTCH4 gene

44. NOTCH4 gene

45. NOTCH4 gene

46. NOTCH4 gene

47. NOTCH4 gene

48. Catechol-o-methyltransferase(COMT) gene

49. Catechol-o-methyltransferase(COMT) gene

50. Catechol-o-methyltransferase(COMT) gene

51. Apolipoprotein E(APOE) gene

52. Apolipoprotein E(APOE) gene

53. Apolipoprotein E(APOE) gene

54. Apolipoprotein E(APOE) gene

55. Apolipoprotein E(APOE) gene

56. Genetics of Scizophrenia :DNA
variation
• Evidence for a substantial genetic contribution comes from family, twin and
adoption studies but the underlying causes and pathogenesis of the
disorder remains unknown.
• The past few years have witnessed marked progress in our understanding
of genetic risk at the level of DNA variation, which has been largely driven
by applying advanced genomic technologies to very large samples.
• There is evidence that risk variants occur across the full allelic frequency
spectrum, many of which are associated with other neuropsychiatric
disorders.
• Moreover, genetic associations involving different classes of mutations have
now implicated specific biological pathways in disease pathogenesis.

57. recent advances in schizophrenia genetics
• de novo mutation,
• rare copy number variation (CNV),
• rare single nucleotide variant (SNV, defined as point
mutations with a frequency less than 1%)
• and small insertion/deletion (indel) mutations
• and single nucleotide polymorphisms (SNPs, defined as
point mutations with a frequency greater than 1%)

58. Schizophrenia risk alleles

59. Copy number variations implicated in schizophrenia

62. • Abnormal production or reaction to the important
chemical neurotransmitter dopamine and maybe
others.
• Dopamine is responsible in sending messages
through the brain and effects how the brain
perceives things.
• Imbalance between dopamine and serotonin.
Brain chemical imbalance:

64. HYPOTHE
SIS

65. Lets remind ourselves how
neurotransmitters work

66. DOPAMINE HYPOTHESIS
The Dopamine hypothesis states that the
brain of schizophrenic patients produces
more dopamine than normal brains.
–Evidence comes from
–studies with drugs
–post mortems
–pet scans

67. Normal Level of
Dopamine In The
Human Brain
Elevated Level of
Dopamine In The Brain of
a Schizophrenic Patient
(specifically the D2
receptor)
 Neurons that use the transmitter ‘dopamine’ fire too often and transmit
too many messages or too often.
 Certain D2 receptors are known to play a key role in guiding attention.
 Lowering DA activity helps remove the symptoms of schizophrenia

68. Etiology of Schizophrenia - Neurodevelopment
Model
• Neurodevelopmental model supposes in
schizophrenia the presence of “silent lesion” in the
brain, mostly in the parts, important for the
development of integration (frontal, parietal and
temporal), which is caused by different factors
(genetic, inborn, infection, trauma...) during very
early development of the brain in prenatal or early
postnatal period of life.

69. • Stress inducing environmental factors such as
social pressure, physical or sexual abuse, loss of
loved ones, hormones, malnutrition, and early
exposure to viruses.
• The major brain changes that occur during
puberty has also been identified as a possible
contributing factor.
Environmental factors

70. TABLE 1. Single-Nucleotide Polymorphisms (SNPs) in 33 Genes
Assayed in 130 Families and Associated With Schizophrenia or
Related Phenotypes in Previous Studies
Gene SNP Identifiers Associated (p<0.01) With at
Least One Endophenotype in
Current Study
ADRBK2a
rs576895, rs558934, rs5761116
AKT1a
rs2494732, rs1130214 rs2494732b
BDNF rs6265
CACNG2a
rs2267341, rs2283981,
rs738518
CHRNA7 rs3087454
COMTa
rs737865, rs4680
DAOa
rs2070587, rs3741775
DAOAa
rs1341402, rs239119, rs778294
DGCR2a
rs2072123, rs807759
DISC1 rs3738401, rs2793092,
rs2793091, rs2492367,
rs1000731, rs821597,
rs4658971, rs843979, rs821616
rs821597b
, rs843979

71. Gene SNP Identifiers Associated (p<0.01) With at Least
One Endophenotype in Current
Study
DRD3a
rs2134655, rs963468, rs6280
DTNBP1a
rs1040410, rs760666, rs2619539,
rs3213207, rs1011313, rs2619528,
rs2619522, rs1018381, rs909706
ERBB4a
rs7598440
GABRB2a
rs187269, rs252944, rs194072,
rs1816072, rs1816071
GAD1a
rs2241165, rs3791850
GRID1a
rs2814351
GRIK3 rs3767045
GRIK4a
rs948028, rs2852217, rs879602,
rs1954787, rs4935752, rs6589846,
rs433110, rs7111184, rs2156635,
rs949054
rs948028
GRIN1a
rs11146020 rs11146020b
GRIN2Ba
rs1805502, rs890, rs1805247,
rs1806201, rs7301328
GRM3a
rs6465084, rs2237562, rs1468412
HTR2A rs7333412, rs2296972, rs659734,
rs6313
rs6313b
TABLE 1. Single-Nucleotide Polymorphisms (SNPs) in 33 Genes
Assayed in 130 Families and Associated With Schizophrenia or
Related Phenotypes in Previous Studies

72. Gene SNP Identifiers Associated (p<0.01) With at Least
One Endophenotype in Current
Study
HTR7a
rs12412496
NCAM1 rs1943620, rs1836796, rs1821693,
rs646558, rs2303377
NEUROG1a
rs2344485, rs2344484
NOTCH4a
rs422951, rs520692, rs915894
PPP1R1Ba
rs4795390, rs879606, rs907094,
rs3764352
RGS4a
rs2661319, rs2842030
SLC18A1 rs1390938, rs2270637, rs2270641,
rs17092104
rs17092104b
SLC6A3a
rs11564773, rs6876225, rs2550936,
rs6347, rs11564759, rs11564758,
rs2963238
rs11564773b
, rs11564758b
SP4 rs11974306, rs12668354,
rs12673091
rs12668354b
TAAR6a
rs8192625, rs4305745, rs6903874
ZDHHC8a
rs175174
TABLE 1. Single-Nucleotide Polymorphisms (SNPs) in 33 Genes
Assayed in 130 Families and Associated With Schizophrenia or
Related Phenotypes in Previous Studies

73. Is Schizophrenia Genetic?
• The only gene strongly connected to
schizophrenia is a gene on chromosome
22 named COMT. When abnormal, COMT
depletes the frontal lobes in the brain of
the neurochemical dopamine, causing
hallucinations and an impaired sense of
reality, both symptoms of schizophrenia.
• Not entirely: there are certain genes that
contribute, but onset depends on the environment
around the individual.

74. Can Schizophrenia Be Inherited?
• No, not specifically. There is one gene linked to
the disorder; however, little heredity is found in
schizophrenia.
• The highest instance of there being
two cases of schizophrenia in a family is
between twins, and the instance of that is
less than 50%, suggesting that
schizophrenia is not inherited. Again, it
depends on the environment around the
individual.

75. “If you talk to God,
you are praying;
if God talks to you,
you have schizophrenia”

76. “Human beings are ultimately
nothing but carriers-passageways-
for genes.
They ride us into the ground like
racehorses from generation to
generation. Genes don't think about
what constitutes good or evil.
They don't care whether we are happy or
unhappy. We're just means to an end for them.
The only thing they think about is what is
most efficient for them.”
Haruki Murakami, 1Q84