Assessing the extent of genetic versus environmental contribution can be done using twin studies and adoption studies. Certain classical modes of transmission, such as X-linked recessive, can be recognised by studying the segregation of diseases through pedigrees. Genetic markers can be used to localise susceptibility genes to particular chromosomal regions. Linkage studies trace marker inheritance through families and provide an approximate localisations. Association studies use unrelated cases and controls to identify markers very close to susceptibility genes. Other methods detect the presence of insertions or deletions - copy number variants. Sequencing is intensive and expensive but it is now becoming feasible to sequence whole genomes or exomes. Functional studies measure the effects of genetic variation on gene expression and protein functioning.
Genetic factors make a substantial contribution to th risk of bipolar disorder. The nature of the effect is unknown but it is assumed that a number of different genes may contribute to risk. one or more may be located on the X chromosome. Genome-wide association studies have produced replicated evidence for the effect of two genes, CACNA1C and ANK3. Other possible candidates include DISC1 and BDNF.
Twin and adoption studies have demonstrated a genetic influence on predisposition. Also, children of the normal monozygotic cotwins of schizophrenics have a similar risk of schizophrenia as do the children of the schizophrenic parents (supporting a genetic aetiology). It is assumed that a number of different genes contribute to risk.
A large Scottish pedigree has been described in which many subjects have a translocation between chromosomes 1 and 11 and suffer from schizophrenia or other psychiatric illness. The breakpoint on chromosome 1 goes through a gene named DISC1 ("Disrupted in schizophrenia 1"), and association studies of DISC1 have been positive in other samples. Abnormalities of DISC1 may interfere with neuronal development.
A deletion of part of chromosome 22 causes velo-cardio-facial syndrome (VCFS) and some patients with this also suffer from a psychosis indistinguishable from schizophrenia. Indeed in some cases the psychosis is the only abnormality which comes to attention and in a cohort of unselected schizophrenics approximately 1% will turn out to have VCFS. VCFS thus represents a rare genetic cause of schizophrenia. It is possible that genes in this region may influence susceptibility to psychosis in other cases. COMT lies in this region and was originally claimed to be associated with schizophrenia but is now thought to influence prefrontal cognitive function.
Positive association studies have been replicated for the genes for neuregulin and DAOA. Neuregulin interacts with DISC1 and is also involved in neuronal development. DAOA (d-amino acid oxidase activator, previously called G72) may be involved in the metabolism of d-serine, an NMDA glutamate receptor agonist, and has also been claimed to be associated with bipolar disorder. PCM1 shows association with schizophrenia and interacts with DISC1 to control neuronal migration.
Studies of copy number variants (CNVs - deletions and duplications) show that in addition to the VCFS deletion CNVs are generally more common in subjects with schizophrenia than in controls. CNVs affecting NRXN1 (neurexin 1) are associated with schizophrenia. Deletions at 15q11.2 and duplications at 16p11.2 increase risk.
Family, twin and adoption studies have demonstrated a genetic influence on the predisposition to alcoholism. The mode of transmission is unknown and it is not clear whether single gene effects or polygenic effects occur.
About 50% of south-east asians do not have mitochondrial aldehyde dehydrogenase 2 isoenzyme, which is involved in the normal metabolism of ethanol. In such individuals the consumption of small amounts of alcohol causes unpleasant symptoms (facial flushing, etc.) and this causes them to avoid alcohol. So the mutation which deactivates ALDH2 indirectly protects against the development of alcoholism.
Some association studies suggest involvement of alcohol dehydrogenase 4 (ADH4).
This is a rare syndrome characterised by motor and vocal tics and sometimes involving coprolalia. Some cases are probably due to an autosomal dominant gene. Even though the mode of transmission appears simple, linkage studies investigating a large proportion of the genome have to date been negative.
There is reasonable evidence for a genetic contribution, and association studies have suggested that variation of the dopamine D4 receptor (DRD4) and dopamine transporter (DAT) genes may affect susceptibility.
In addition to attempts to identify genes which contribute aetiologically to disease, there is increasing interest in trying to find common polymorphisms which may affect response to treatment in terms of efficacy or side effects. For example, it is claimed that variation of the gene for the serotonin transporter, which is responsible for the reuptake of serotonin into nerve endings, may affect response to SSRIs. Likewise, variations of genes for serotonin type 2 receptors, in particular HTR2C, may influence not only treatment response to clozapine and other antipsychotics but also the severe weight gain which can occur with clozapine and olanzapine. One study showed that the response of alcoholics treated with bromocriptine was influenced by the genotype of the gene coding for the dopamine D2 receptor.
40% of cases have unknown aetiology. Single gene disorders can be divided into neurodegenerative, syndromic and non-syndromic. Many chromosomal (Downs syndrome) and genetic (phenylketonuria) abnormalities cause learning disability. Note the example of phenylketonuria showing the way in which genes and environment (phenylalanine in the diet) can interact.
The mutation responsible for the fragile X syndrome has been identified and the gene in which it occurs has been named FMR1 (Fragile-X Mental Retardation). Its transmission is complex, since although the mutation can act as an X-linked recessive it "gets worse" as it passed on through different generations - a trinucleotide repeat sequence (CGGn) enlarges.
There is strong evidence for a genetic basis for this condition, and it is thought that abnormalities of a variety of different genes may combine to cause disease. Mapping studies are underway. Rarely cases are due to mutations affecting the neuroligin or neurexin 1 genes. The autism phenotype can also occur with fragile X syndrome and mutations of MECP2 which more usually cause Rett syndrome. 1% of subjects with autism have a deletion at 16p11.2. Recent studies implicate the cell adhesion molecules cadherin 9 and 10 in the risk of autism itself and in the susceptibiilty to produce stereotyped conversation in normal subjects.
Senile-onset Alzheimer's disease is a common cause of dementia with a similar prevalence to multi-infarct dementia. Presenile Alzheimer's disease is a rare presenile dementia which is inherited as an autosomal dominant disease and causes similar changes in the brain, notably neurofibrillary tangles (rich in tau protein) and amyloid plaques. Identical lesions also occur in patients with Downs syndrome (trisomy 21) in middle-age. The gene which codes for the protein forming this amyloid is on chromosome 21q, and following linkage studies it was shown that mutations in this gene (for APP - amyloid precursor protein) account for a small minority of cases of presenile Alzheimer's disease. Other presenile cases are due to mutations in presenilin 1 (PS1) and presenilin 2 (PS2). The presenilins are involved in the normal processing of APP.
Association studies show that the risk of senile onset Alzheimer's disease is strongly influenced by the genotype of apolipoprotein E. Three alleles are commonly found: e2, e3 and e4. Inheriting one copy of the ApoE-e4 allele trebles the risk of Alzheimer's, while inheriting a second copy trebles the risk again. Apolipoprotein E binds to the amyloid precursor protein and to neurofibrillary tangles, and this may provide some clue to the aetiology of senile onset Alzheimer's disease.
Association studies suggest that the neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. SORL1 directs recycling of APP. Preliminary studies suggest that GAB2 may influence risk in subjects who are APOE4 carriers.
It is assumed that other loci may also influence susceptibility to late onset Alzheimer's disease, and linkage studies suggest that such loci may be present on chromosomes 10 and/or 12. Recent association studies have implicated CLU, PICALM, CR1 and BIN1.
Molecular genetic insights have allowed the construction of mouse models of Alzheimer's disease, so that new treatment approaches can be tested.
These are degenerative brain diseases with spongiform changes in which variable degrees of amyloid deposition occur as a result of the accumulation of prion protein derviatives. Some forms of these diseases occur as autosomal dominant disorders within families: Gerstman-Straussler syndrome, fatal familial insomnia, familial Creutzfeld-Jacob disease (CJD). In these cases there are mutations in the prion protein gene which cause an abnormal form of the protein to be produced.
Other prion diseases, for example kuru (and in animals BSE), are transmitted horizontally and occur in subjects with the genetically normal form of prion protein. The abnormal prion protein acts as the "infective agent" and stimulates a conformational change in the host protein, thus setting off a "chain reaction". In Britain a small number of atypical cases of CJD have recently occurred in young subjects, leading to suspicions that they are related to BSE. These cases show pronounced amyloid depositon, a longer time course, lack of characteristic EEG changes and are seen in unusually young subjects. This is now termed "variant CJD". Following partial digestion the abnormal protein from these cases has a similar electrophoretic pattern to that found in BSE.
An equivalent transmissible spongiform encephalopathy occurs in deer and elk, where it is termed "chronic wasting disease". This is spreading through North America and there have been reports of hunters and venison eaters developing CJD.
Most cases of CJD occur sporadically, with no known risk factors.
The diagram shows a simplified graphical representation of possible mechanisms leading to the deposition of amyloid in these diseases.
| Normal amyloid precursor protein (APP) is soluble |
|
| Mutations in the APP gene can lead to abnormal forms of the protein which can go on to form amyloid |
|
| ApoE e2 may reduce the probability of amyloid formation from APP |
|
| ApoE e4 may increase the probability of amyloid formation from APP |
|
| Normal prion protein is soluble |
|
| Mutations in the prion protein gene (PRIP) may lead to abnormal products which can form amyloid |
|
| In transmitted prion disease, prion protein in an abnormal conformation can induce a conformational change in the normal protein |
|
February 2012
http://www.mds.qmw.ac.uk/statgen/dcurtis/lectures.html
Dave Curtis (david.curtis@qmul.ac.uk)
