Although our genetic information crucially contributes to our appearance, our properties and preserves our life, it also contributes to the susceptibility to diseases. Improper protein coding or regulation by the genetic information can lead to a lack or excess of the corresponding proteins, or the occurrence of wrong or defect proteins. This in turn can cause disease or at least increase the risk to develop the disease. The better understanding of participating genes and proteins in disease development can lead to advances in abatement and healing and therefore the identification of such genetic factors is of high importance. Additionally, our genetic makeup can not only partly explain the predisposition to a disease, but also individual reactions to drugs.
In this chapter we will concentrate on the genetic origin of diseases. Therefore, we will first describe simple monogenic diseases that follow quite straightforward the laws of Mendelian segregation and are characterized by a unique gene-disease relation. In section2.3.2, factors complicating this simple pattern will follow and sections2.3.3 and 2.4 focus on complex diseases.
2.3.1 Classical monogenic diseases
Genetic causes are easily determined forclassical monogenicorMendelian diseases.
This kind of diseases follows simple Mendelian inheritance patterns (section 2.1.5) and is caused by one gene only with penetrances nearly 0 or 1. The penetrance relates a genotype and a phenotype to each other and is defined as the conditional probability that a person with a particular genotype develops the phenotype of interest. For dis-crete phenotypes, we can express the penetrance byfgenotype =P(phenotype|genotype).
When a disease causing genotype always results in the development of the disease, the conditional probability equals 1 and we have complete penetrance. In Mendelian diseases where no further factors with an influence to the disease exist the penetrances for the remaining genotypes equal 0. We can distinguish different Mendelian modes of inheritance of the disease: dominant, recessive and codominant (section2.1.5). Further-more, the location of the genetic factor plays an important role. In the following, we assume that we have a biallelic locus with normal alleleAand disease causing varianta.
A classical monogenic disease is calledautosomal dominantwhen the influencing gene is located on one of the autosomes and only oneaallele at that locus suffices to cause the disease. Expressed in penetrances, we have fAA = 0 and fAa =faa = 1. When the gene lies on an autosome but two disease causing a alleles are required for disease develop-ment, we have a classical autosomal recessivedisease. In that case, the penetrances equal fAA = fAa=0 and faa = 1. Chorea Huntington is an example for an autosomal dominant disease, while cystic fibrosis follows autosomal recessive inheritance patterns.
However, since heterozygous genotypes need not necessarily express the same phenotype as one of the homozygous, a codominant inheritance, with each genotype showing its own phenotype, can occur as well. A particular form of codominance is an additive mode of inheritance, with each susceptibility allele at a locus equally contributing to the phe-notype or disease risk. An example for a codominant inheritance is a particular point mutation in the beta-hemoglobin gene (HBB) that replaces the normal hemoglobin allele HbA by a sickle cell hemoglobin allele HbS. This results in a sickle shape of red blood cells (sickle cell disease). Sickle-shaped cells can cause pain and organ damage by block-ing small blood vessels and they die prematurely (http://ghr.nlm.nih.gov/gene/HBB).
However, in heterozygous carriers we have genotype HbA/HbS so that both hemoglobin types are expressed and only 25%-40% of the erythrocytes are affected by the modified sickle-cell form. Therefore these persons show only few recognizable clinical symptoms.
On the contrary, in homozygous individuals with genotype HbS/HbS all red blood cells are sickle-shaped, so that in general a shortage of red blood cells (anemia) occurs and serious symptoms in further organs (sickle cell anemia). Hence, the severity of the dis-ease differs between heterozygous and homozygous individuals. Disdis-ease causing loci can be located on the sex chromosomes as well. However, we will not handle this here since our methods are restricted to the examination of autosomal markers.
Monogenic diseases are in general rare, occurring in less than 1 out of 1000 persons.
This low disease frequency can be explained due to occurrence of the disease in early childhood with severe chronic progress resulting in reduced fitness or even lethal con-sequences. By investigating family data, genes of classical monogenic disease can be easily detected and many are already successfully examined. Although only one gene is involved in monogenic disease, one, several or even many alleles of that gene can cause disease development.
2.3.2 Departure from simple Mendelian segregation
The model of Mendelian segregation is useful to demonstrate the principle of genetic disorders. Unfortunately, even monogenic diseases are rarely subject to such straight-forward models of inheritance (Bickeb¨oller and Fischer,2007). Several factors exist that modify this simple pattern and make the model more complicated.
One of these issues is the deviation of penetrances from the simple 0 and 1 rule. On the one hand it is possible, that not all individuals with a specific genetic predisposition necessarily develop a corresponding phenotype, but that it establishes only in a fraction of the carriers. This effect is denoted as reduced penetrance. Another phenomenon concerning penetrances is phenocopies. This is the case when the affection occurs as well in non-carriers of the genetic disposition, ascribed by other genetic and non-genetic factors with an impact to the disease development. We observe penetrances 0< f <1.
Furthermore, the penetrance can vary by age, with a higher probability of disease de-velopment with older age (e.g. in cancer).
In addition, heterogeneity can affect the inheritance of disease. This compasses al-lelic heterogeneity, denoting that different alleles of one gene can be responsible for the same disease, andlocus heterogeneity, meaning there can be different responsible genes for disease development. Phenotypic heterogeneity and pleiotropy is given when the same disease shows diverse clinical characteristics in different individuals, or
when one gene causes different symptoms or even different phenotypic traits. Hetero-geneity can occur between different families (intra-familial heteroHetero-geneity), but also within families (inter-familial heterogeneity). A useful tool to handle heterogeneity is to homogenize study samples with respect to a disease by defining subgroups that can be examined more easily. For many diseases, e.g. cancer diseases or Alzheimer’s disease, concentrating on individuals with early-onset is useful for example.
Several other complicating factors exist, e.g. anticipation, genomic imprinting, gender restriction, X-inactivation in women, germ cell and somatic cell mosaics. These factors cannot be covered with the analysis methods in this thesis and are hence not covered here.
2.3.3 Complex diseases
Most common diseases such as cancer, cardiovascular diseases, allergies or psychiatric diseases are complex diseases that are not directly inherited according to classical Mendelian mechanisms but characterized by a complicated interplay of numerous genetic and environmental factors (Buselmaier and Tariverdian,1999). This complexity involves different forms of heterogeneity listed above, reduced penetrance and pheno-copies, and can be complicated by additional other principles not handled in this thesis.
In most complex diseases we have no strict genetic causation, but rather a genetic predisposition for the disease given by multiple genetic factors and the manifestation of the disease depends on the influence of exogene factors during lifetime. This results in a misty relationship of genotype and phenotype, with no apparent inheritance pattern and even not necessarily an obvious aggregation in families. Disease etiology can be compared to a Marshalling yard: while the direction and different possibilities to change the switches are specified by the genetic factors, the environmental exposures determine which track is taken (Buselmaier and Tariverdian, 1999).
When only a low number of genetic markers is responsible for disease development, we say that the disease is oligogenic. When a high number of disease causing loci is involved the disease is polygenic. Polygenic diseases with an additional environmental contribution are denoted as multifactorial or complex. As already mentioned in the introduction, from time to time, even for complex diseases clear Mendelian subforms with one underlying mutant gene (major gene) with a strong effect can be identified.
However, since these major genes of complex diseases are extremely rare and affect only a very small part of the affected people, we concentrate on oligogenes and polygenes as well as further modifying factors. A modifying factor is defined as a factor that influences the effect of another factor.
Although these genes have a much lower penetrance than the major genes, the suscep-tibility gene variants occur more often and affect a larger proportion of the population.
Therefore, their investigation is highly important. For Alzheimer’s disease for example, several oligogenes are identified besides the major genes, e.g. the Apolipoprotein-E (OMIM, 2012 #107741,#104310). Although this gene has a much lower penetrance than the major genes with a risk increased by factor 3, this gene mutation affects 15%
of the population and is responsible for 30%-50% of all Alzheimer patients (Farrer and Cupples, 1998).
Detecting “non-major” genes of complex diseases may support our understanding of the underlying pathogenic mechanisms. Furthermore, the hope for the future is that it may facilitate to derive risk prediction models, new preventive strategies and more effective therapies and medications. However, it is still a long way to get there and we will concentrate here on the first step to identify the genetic risk factors. Unfortunately, such “non-major” genetic factors in common diseases etiology are difficult to reveal due to the complex mechanism involving the high number of factors with only small effects and interactions between them.
In the following section we will take a more detailed look at the complexity of the architecture of common diseases involving numerous genetic and non-genetic factors.
This complexity involves the coordinated work of genes within biological pathways, genes interacting with each other (GxG) and the environment (GxE). Since the focus of this thesis is the integration of biological pathway information into a genetic analysis and the examination of GxE interactions, we will mainly focus on these two principles and touch on the topic of GxG only shortly.