牛康衛 08301016018復旦大學上海醫學院 2009.12

A psychiatric disorder that makes the patient have an altered sense of reality

Sx must have been present for one month in a period of six months of dysfunction.

Anything shorter than this is a schizophrenifom disorder

Positive Sx auditory and visual hallucinations paranoid delusions disorganized speech

Negative Sx Flat affect Alogia (speech poverty) Anhedonia Asociality Avolition

significant social or occupational dysfunction word salad (incoherent speech) avolition (apathy)

In the United States, the APA's DSM-IV-TR is used, while in much of the rest of the world, the WHO's ICD-10 is used to determind the criteria. (Although the two mostly overlap)

DSM-IVdiagnosis of schizophrenia must: Have 2+ of aforementioned Sx for a the better part of a

month Have signs of the disturbance for at least

6 months (with at least one month of Sx) Must have social or occupational

dysfunction (or dysfunction in self-care)

The DSM-IV and ICD-10 have defined subtypes of schizophrenia:

Paranoid type - only with delusions and hallucinations Disorganized type - thought d/o and flat affect are prese

nt at the same time Catatonic type - immobile or have purposeless movement Undifferentiated type - psychotic Sx are present, but abo

ve not met Residual type - Sx are present, but with low intensity Post-schizophrenic depression Simple schizophrenia - progressive development of nega

tive Sx with no prior psychotic episodes.

Family history or ties to schizophrenia Prenatal problems

e.g., mother was malnourished, had viral infection, took medications (diuretics, etc)

Family member has history of psychotic disorder (such as delusional disorder)

You have problems with drug or alcohol Shizophrenia causes problems? Problems cause schizophrenia?

Age of onset: Late adolescence and early adulthood

Dopamine imbalance This is the most commonly researched

Genetics (our focus) Prenatal and early environment Neurobiology

All factors interact to trigger the manifestation of schizophrenia.

Genetics must be considered in conjunction with environment

al factors Multifactorial (caused by interactions of several gene

s) It is still an area that is new and open to much mor

e further study Though it is considered to be a major contribu

ting cause, studies have only begun to be performed to determine the genetic effects with respect to schizophrenia.

Relationship Risk

Monozygotic twins 40-50%

Dizygotic twins 17%

Children 13%

Siblings 10%

Half siblings 6%

Grandchildren 5%

Nieces, Nephews 4%

Aunts, Uncles, Cousins 2%

General Population 1%

In the upcoming portion we will be talking about different studies that analyze the genetic factors behind schizophrenia.

To understand these studies, we have to understand a few terms.

Twin studies are significant between they allow researches to separat

e what is affected by environment and genes. especially when twins are separated at birth

different environment, but same genes Monozygotic twins share nearly 100% of genetic polym

orphisms Dizygotic twins share about 50% of polymorphisms

Phenotype "Outward, physical manifestation" of the organism in other words what we see (either macroscopically

or microscopically) Genotype

"Internally coded, inheritable information" carried within genes of organisms

"Instructions" on all aspects of biological life in other words what is encoded

Karyotype A "map" of the chromosomes in the human body

Genetics is only a "major" influence There are may schizophrenia patients that do not have a fa

mily history. Twin studies

Heritability risk at ~80% Increased risk even when raised apart

Schizophrenic phenotype genetically influenced not genetically determined Gene variants are usually within normal limits

A karyotype is a "picture" of all 23 chromosomes and the X or Y in a human genome.

In a series of studies published in July 2009 in Nature, A “hot spot” was found on chromosome 6p22.1

On short arm of chromosome 6, at extended MHC region Has on it a histone gene cluster Related to control of DNA transcription and repair Related to antimicrobial defense, immunity Controls when and how genes turn on/off

Research by Shi et al show: “Schizophrenia is significant associated with

single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6”

This region has a histone gene cluster, and also a some genes related to immunity

This could imply etiological linkage to: Chromatin modification, transcriptional regulation,

autoimmunity, and/or infection.

Research by the Stefansson et al: Based on genome-wide studies of similar

populations as Shi et al Studied specific Copy Number Variations (CNVs)

CNVs are areas of DNA where copy-number differences are found by comparing multiple genomes

Can be either inherited or caused by de novo mutations, such as deletions, duplications, inversions, or translocations.

Research by Stefansson et al: On these MHCs there are a higher than usual

frequency of risk alleles

Research by the International Schizophrenia Consortium: Shows that there is a linkage between

schizophrenia and bipolar disorder Also found in sequences on chromosome 6

Methods by Shi et al: Tested two populations: European-ancestry (2,681

cases), and African-American (1,286 cases). Appropriate controls were implemented of similar numbers.

Methods by ISC: Tested European population (3,322 cases) with 3,587

controls. Methods by Stefansson et al:

Tested European population (2,663 cases) 13,498 controls from eight locations

There is still a lot of room for more research into the genetic background of schizophrenia

The information presented here was just one tiny fraction of the research that is already out there