Schizophrenia and Genetic

Schizophrenia

and Genetics

Narjes Khatoon shabani sadr

Provided for: behavioral genetics-doctor Forughmand

Introduction

• The symptoms of schizophrenia can be categorized into three wide-ranging groups.

1. Positive symptoms2. Negative symptoms3. Cognitive symptoms

Symptoms

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.

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

• No one knows the exact causes of Schizophrenia, but multiple possible factors have been discovered.

• These factors include:1. Genetics2. Brain chemical imbalance3. Environmental factors4. Family history

Causes

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

Genetic predisposition

Neurodevelopmental abnormalities and target features

Further brain dysfunction and schizophrenia

Neurodegeneration and schizophrenia

Etiologic pathway

Early environmental insults

Later environmental insults

psychosis

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

Genetics of Scizophrenia

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.

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.

Twin, adoption and family studies

Twin, adoption and family studies

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).

family studies

family studies

Risk of Developing Schizophrenia (in percents) from SCHIZOPHRENIA GENESIS

family studies

Genome-wide studies

Genome-wide studies

new findings promise new insights

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.

Candidate gene studies: gene studied

Candidate gene studies: gene studied

Brain-derived neurotrophic(BDNF) gene






Epidermal growth factor(EGF)gene




NOTCH4 gene

NOTCH4 gene

NOTCH4 gene

NOTCH4 gene

NOTCH4 gene

NOTCH4 gene

Catechol-o-methyltransferase(COMT) gene



Apolipoprotein E(APOE) gene





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.

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%)

Schizophrenia risk alleles

Copy number variations implicated in schizophrenia

• 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:

DOPAMINE HYPOTHE

SIS

Lets remind ourselves how neurotransmitters work

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

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

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.

• 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

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 StudyADRBK2a 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

Gene SNP Identifiers Associated (p<0.01) With at Least One Endophenotype in Current

Study

DRD3a rs2134655, rs963468, rs6280DTNBP1a rs1040410, rs760666, rs2619539,

rs3213207, rs1011313, rs2619528, rs2619522, rs1018381, rs909706

ERBB4a rs7598440GABRB2a rs187269, rs252944, rs194072,

rs1816072, rs1816071GAD1a rs2241165, rs3791850GRID1a rs2814351GRIK3 rs3767045GRIK4a rs948028, rs2852217, rs879602,

rs1954787, rs4935752, rs6589846, rs433110, rs7111184, rs2156635, rs949054

rs948028

GRIN1a rs11146020 rs11146020b

GRIN2Ba rs1805502, rs890, rs1805247, rs1806201, rs7301328

GRM3a rs6465084, rs2237562, rs1468412HTR2A rs7333412, rs2296972, rs659734,

rs6313rs6313b



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



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.

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.

“If you talk to God,

you are praying;

if God talks to you,

you have schizophrenia”

“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

Health & Medicine

Schizophrenia and Genetic