The History Of Autosomal Dominant Inheritance

Published Date: 02 Nov 2017

Institute of Psychiatry

MSc Neuroscience

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* Explain the differences between Mendelian and non-Mendelian disease. Using one neuropsychiatric disorder (e.g. schizophrenia, ADHD, alcohol dependence etc.) discuss the progress made so far in understanding the genetic architecture of that disorder.

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Introduction

Schizophrenia is clinical syndrome based on the presence of operational criteria such as delusion, hallucinations, apathy and cognitive difficulties resulting in dysfunction and progressive deterioration66. It is an etiologically heterogeneous syndrome that usually manifests in adolescence and early adulthood.

Genetic inheritance concerns the passing on of genetic material from parents to offspring by way of sexual reproduction, with the child receiving one set of set genetic material from each parent. Inherited characteristics, for features such as eye colour or hereditary disorders may be specific to one gene and are directly passed to offspring: Mendelian inheritance; or there may be a number of genes that contribute to the manifestation of a characteristic; non-Mendelian inheritance.

Mendelian inheritance

Based on the pioneering work of Gregor Mendel’s experiments on inherited characteristics of pea plants, the study of genetics still retains many of the features as described by Mendel.

In Mendelian inheritance, inherited genetic characteristics are known as the genotype, with characteristics located on individual genes or at specific locations on the gene known as loci.

Located at each locus these are alleles: variants of one of a number of alternative forms of the same gene. These may be dominant (represented figuratively by an upper case character e.g. A) or recessive (represented by a lower case character of the same type as the dominant allele e.g. a). During reproduction, parental genes mix producing offspring in relatively well defined ratio proportions of both genotype and observable characters: the phenotype. The dominant allele will always be expressed in a heterogeneous and homogenous genotypes (AA and Aa respectively), whereas the recessive character will only be expressed in the context of homogenous genotype for the recessive trait (e.g. aa). Phenotypes of dominant heterogeneous and homogenous individuals will appear the same.

Mendelian inheritance may be summarized as a particular genotype at one locus is necessary and sufficient for the character to be expressed in the offspring1.

The number of individuals carrying a particular allele or genotype which also expresses the phenotype is known as penetrance

Mendel’s laws

From his observations Mendel devised two laws1:

The Law of Segregation: each individual carries a pair of genes or alleles for a character; during reproduction a parent will pass a one randomly selected allele to its offspring. The offspring will then posses its own pair of alleles, one from each parent. The resulting phenotype will depend upon which alleles have been passed on.

Law of Independent Assortment: inherited characters states that separate genes for separate characters are passed independently from parents to offspring, i.e. the selection of one gene for one trait are inherited regardless of other inherited characters for other traits.

Mendelian pedigrees

Inheritable characteristics include both features such as height but also gene defects and mutations representing a range of disorders. There are presently over 4000 recorded human genes related to single gene defects or mutations which may be passed on to subsequent generations in a variety of ways.

Known as pedigrees, Mendelian inheritance features are summarized as follows1, 2, 3, 4:

Autosomal dominant inheritance

the disease trait is located on the dominant allele

only one mutated allele is necessary for inheritance: only one parent needs to carry the mutation,

May be inherited from either sex, and can affect either sex.

The genotype of the individual may be dominant homozygous or heterozygous. Assuming the offspring is heterozygous, the likelihood of a child inheriting the mutated is 50%. This is not to say the offspring will develop the disease, however.

Examples: Huntingdon’s disease, Charcot-Marie Tooth disease. 5

Autosomal recessive inheritance

disease trait is located on a recessive allele

two copies of the allele are necessary for inheritance: a homozygous recessive genotype. Either parent may be a sufferer if they have the recessive homozygous genotype or they may be asymptomatic carriers of the disease in the case of heterozygous alleles, in which case the parents’ genes will contain the mutation, but the disease will not manifest.

Usual that people with these diseases are born to unaffected parents.

Either sex may be affected

inheritance risk is 25%, independent of any siblings who may have inherited the mutation.

Examples: sickle cell anaemia, cystic fibrosis6

X-linked dominant inheritance

mutation is found on the dominant allele on X chromosomes only. The

mutation may be inherited from either parent but it is usually only one parent who is affected.

Either sex may be affected, with a 50% chance of inheritance for the child of an affected female parent, and in the case of an affected male parent, all his daughter but none of his sons will inherit

Examples: Rett’s syndrome, fragile X syndrome7

X-linked recessive

mutation is found on the recessive allele of an X chromosome only

Males are mainly affected, usually born to unaffected parents; the mother being the unaffected carrier

no male to male transmission.

Examples: red-green color blindness, Duchene muscular dystrophy8

Y-linked

only males are affected

affected male always has an affected father, except in cases of a new mutation. 100% of sons of an affected father will inherit the affected allele.

Examples: male infertility, colour blindness9

Mitochondrial

both sexes are affected

usually inherited from an unaffected mother, although de novo mutations are often a cause, in which case the mother does not have the mutation.

Fathers do not transmit the mutation to their children.

Highly variable clinical manifestations.1

Single gene disorders as detailed above concern thousands of genetic traits and disorders although some are exceedingly rare.

Non-Mendelian inheritance and diseases

Monogenic diseases: one gene, one disorder show classic Mendelian features, with rare but directly causative alleles10.   By comparison, alleles in non-Mendelian disorders have common variants, meaning that there are not directly causative alleles, but rather risk alleles. Due to the high number and common nature of these alleles, identifying those that influence the development of the disease is that much more difficult.

Incomplete penetrance for a known disease in families, where individuals carry the mutated alleles but this is not expressed in their phenotype provides evidence for non-Mendelian inheritance patterns. This demonstration of a continuum of variable expression demonstrates that genes fulfill their functions through a wide variety of interactions with other cellular components. At every stage, DNA is subject to regulation and variation depending upon those factors influencing the expression of proteins and RNA for example, with the internal environment of cells greatly affecting gene expression in addition to influences from other genes.

Advances in technology have lead to greater identification of single gene disorders, allowing appropriate counseling and management of the disorders. By comparison, the complex nature of non-Mendelian diseases and inheritance presents a significant challenge for detection of genotypes due to the influence of multiple genes, internal and external factors on the resulting phenotype.

Phenotypic expressions of diseases are often described with reference to a risk scale: the observed scale of the disease, where the phenotype is either affected or not affected11. Within a population there will be many individuals that have the genotype for a disease but remain unaffected. It is only when a certain threshold of liability is exceeded does the disorder manifest4.

http://www.nature.com/nature/journal/v461/n7265/images/nature08494-f1.2.jpg

Figure 1: Feasibility of identifying genetic variants by risk-allele frequency and strength of genetic effect (odds ratio) 12

Genetic architecture

Genetic architecture refers to the genetic basis of phenotypic traits and comprises of four factors11:

The number of risk alleles that contribute to disease in a population, which may include multiple risk alleles in a single gene.

The frequency in the population of each of the risk alleles. This includes major and minor alleles

The effect size of a risk allele that encompasses the concept of penetrance

The way in which risk alleles interact together, either additively or multiplicative

The heritability of schizophrenia

There is clear evidence from adoption studies and recurrence risks to relatives for a genetic etiology of schizophrenia13,14 in addition to genotyping studies, association studies or linkage studies. Although heritability is high, with some studies putting it as high as 81%15 only a small number of cases have a family history of the disease, ranging from less than one third16 to as low as under 4%17. Other risk factors include including male gender, advanced paternal age, perinatal events and recreational drug use15,16.

The genetic architecture of schizophrenia

Since genomewide association studies (GWAS) have produced strong evidence for over 40 different common diseases that specific DNA sequence differences influences in individual’s genetic susceptibility18. The goal of GWAS is to uncover the basis of diseases, and to provide information on the genetic architecture of these disorders.

As with other non-Mendelian disorders, in schizophrenia one risk allele is not enough. Studies instead look for likely influential genes.

Candidate genes

Genes known to play a role in the disease process to some degree are the most likely candidates to explore a more significant role in the expression of phenotype or a plausible functional role. These studies offer greater power to detect genes of small effects compared to linkage studies. Unfortunately, for psychiatric disorders, the pathophysiologies are unknown, with most candidate gene hypotheses based on the effects of psychiatric medication18. Some examples of candidate gene association studies include investigation connected with dopamine, glutamate and GABA. Despite the exploration into the role of candidate genes in the etiology of schizophrenia, analyses of common variants have proved largely unsuccessful, however19, 20, 21, 22.

Linkage analysis

Linkage analysis has been shown to be good for identifying mongenic diseases, but there have been few successes with regards complex genetic disorders23.

Single nucleotide polymorphisms - SNPs

SNPs are common variants in the nucleotide position on a human genome, approximated to be about one in 3001which some studies publishing findings suggesting several potential SNPs that increase the risk of developing schizophrenia.

A genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown24.

Chromosome 1: DISC 125 shows a rare but interesting result. This disrupts neuronal morphology of cells and several neurodevelopmental pathways.

By contrast, one study26 identified no definitive associations between SNPs and schizophrenia risk. Their study failed to replicate any of the SNPs previously identified in either genome-wide association studies or candidate gene studies as schizophrenia risk factors.

One study, using combined stage 1 and 2 genome-wide analysis27 showed significant associations with schizophrenia for seven loci, five of which were new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2).

As recently as 2012 evidence has been presented that rs2473307, in strong LD with the schizophrenia associated SNP rs2473277, is a functional variant at CDC42 that may increase risk for schizophrenia by reducing expression of CDC4228.

Copy Number Variants - CNVs

Copy number variants (CNVs) are large (typically greater than 1000 base pair) deletions or duplications of the genome that vary in copy number among individuals within a population29,30,31. As CNV analysis is genome-wide, it allows researchers to look for disease association in a variety of ways, with studies showing that rare structural variants are associated with a risk of schizophrenia32,33,34 specifically a moderate risk35,36,37,38.

A microdeletion of chromosome 22q11.2 has been found to confer a substantial risk for schizophrenia39, in addition to a high risk for autism40. This CNV deletes 43 genes, but it is not known which increases risk for mental illness41. A number of studies have suggested that the 22q11.2 microdeletions account for 1-2% of all schizophrenia cases34, 42,43 ,44.

Some studies have identified genomic ‘hotspots’ which harbor multiple structural variants strongly associated with schizophrenia34,45 the common disease-rare allele hypothesis12,46; whilst others indicate that mutations contributing to schizophrenia are not limited to a small number of ‘hotspots’ but rather involve many different genes throughout the genome 33, 34,35,46. The common disease-common allele hypothesis12,45 attempts to explain these findings emphasizing cooperation among multiple, relatively common inherited alleles, each presenting a weak or modest risk, but which when working together to increase the disease risk significantly47.

One study observed an 8 fold increase in frequency of de novo (a spontaneous mutation not presented or transmitted from either parent) CNVs in patients from families with sporadic schizophrenia compared with healthy controls44.

Influences on gene expression

Genetic

There is likely a contributing role from epistasis: the expression of one gene depending on the presence of one or more modifier genes, either as inhibitors of inhibitor genes or promoters for the development of schizophrenia.

Furthermore, epigenetics may help to explain some of the missing heritability that has so far remained undetected in many common disorders48

Cannabis

Several studies found using cannabis in adolescence increases the likelihood of experiencing symptoms of schizophrenia in adulthood49,50,51 with a relative risk of later schizophrenia between two and six fold. It has been presented that that cannabis use appears to be neither a sufficient nor a necessary cause for psychosis, but is a component cause, part of a complex constellation of factors leading to psychosis51.

Evidence presented in 2005 detailed a functional polymorphism in the COMT gene interacted with adolescent-onset cannabis use, to predict the emergence of adult psychosis. Further discussion, however, suggested there may be an alternative causal hypothesis such as preexisting early behavior or cognitive problems may lead psychosis-prone carriers to use cannabis as teenagers52. This was based on findings that individuals with the Val allele were at no main-effect risk for developing psychosis or for taking up the use of cannabis as teenagers53.

Some, hypothesize that the observed gene-environment interaction may be limited to a sensitive period of brain development in adolescence54. There is also the question of whether cannabis use represents a true environmental risk factor or is merely a proxy for unmeasured genes.

Non genetic influences

‘Genetic variants that confer only a small increase risk to disease are individually not useful in predicting a person’s genetic risk to disease’11.

It has been suggested that early impaired social functioning appears to be a risk factor for psychosis, which when taken with attenuated psychotic syndrome (APS) increases this risk55. Individuals with APS are at an increased risk of later developing a psychotic disorder, with transition risks of 18 percent at six months and about 40 percent after three year56. Nearly three-quarters of those who do transition receive a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder57.

Other possible risk factors for the development of early onset psychosis and schizophrenia include urbanicity, childhood adversity58 and birth complications59. These environmental risk factors for schizophrenia seem to have an impact on the age of onset of psychosis in non-familial schizophrenia, but they do not seem to have an impact on familial schizophrenia, however.

Interestingly, there is data that with though the development of some psychiatric and developmental disorders such as non-familial schizophrenia and autism are inherited independently, bad luck appears predicts bad luck as can be seen in families with more than one offspring presenting with the disorder against statistical odds1.

What next?

Despite the progress made so far investigating the architecture of schizophrenia, there is still much to be discovered. GWAS analysis did not identify a large number of associated loci for diseases. What is more likely is that there are possibly thousands of very small individual effects which collectively will account for a significantly increased risk for a certain disorder.

GWAS have found SNPs and CNVs associated with causal variants but these show only a small amount of the variance and even when taken in total, they represent a tiny amount of the genetic variance. Furthermore, SNPs are common but associated CNVs are rare. It is likely that current GWAS will not be able to detect these60.

The PGWASCCC in 200918 presented the challenges for future studies as follows:

Some disorders may not be amenable to GWAS if all risk alleles have very low genotypic relative risks, if genetic risks are conferred by multiple rare SNPs, CNVs may be too small to be readily detected.

Current clinical diagnostic categories may not be adequate

Case subjects may not share risk factors – heterogeneity47 Comparison groups and selection of individuals for GWAS is not clear.

Some disorders may not have detectable main effect of SNPs but instead may be a result of gene-gene or gene-environment interactions

GWAS assays do not consider all common variants.

Provision of information about CNVs and their relationship to disease needs to come about through improved methods.

There are likely to be unknown genetic mechanisms which may change the interpretation of existing and future data.

Not all cases of schizophrenia are dependent upon the presence of highly penetrant mutations61: epistatic interactions62, modifying effects of environmental factors65 and stochastic developmental variation64,65 may all be factors.

As has been shown, there does not appear to be current consensus between hypotheses of ‘hotspots’ for rare but large effecting genes versus the multiple gene-small effect lobby.

An additional risk to further discoveries is the reduced interest in funding for more GWAS60 as there has yet to be published any major breakthroughs.

Despite progress made so far, there are still factors such as de novo mutations to schizophrenia that current literature has yet to address47.

Concerning the validity of previous studies and implications for future research, there needs to be careful consideration of the specificty of populations recruited and the replicability of results

With regards to indications for the identification and specialised treatment as few schizophrenia patients share identical genomic causation, there are potential complications in efforts to personalize treatment regimens26 even though improved diagnostic tools and specialized therapies could have dramatic impacts upon reducing the impact of symptoms of schizophrenia and the progress of the disease.

Ethics and discussion

As with any genetic testing, there needs to be some consideration of the possible ethical impacts on individuals, families and society. This may become even more significant with the dramatic reduction in the cost of testing, the increase in speed of conducting tests and the advent of home testing.

There may be circumstances where individuals are pressured or feel obliged to test for risk genes from families or organizations such as employers or the life assurance industry. What then of the possibility of increased premiums, for example for people with risk genotypes but no associated phenotype?

If known genetic risk factors are detected, this may influence people’s decisions about having children, knowing they may pass on these genetic factors.

Identified genotypes may have a dramatic impact upon individuals' lives, from taking decisive action to minimize risk factors for expression to a passive surrender to a circumstance where a phenotype is never seen but people may not feel able to live the life they would wish for fear of the disease developing.

In summary, there have been some interesting advances in the knowledge of the architecture of schizophrenia in a number of studies, but major breakthroughs have not yet been found. Furthermore, there needs to be careful consideration given to the identification of risk genotypes and its possible impact upon individuals and the wider society.