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Genetic Heterogeneity

Based on various genetic studies, genetic heterogeneity is found to play a role in many complex diseases, where the disease is associated with the effects of more than one gene. Genetic heterogeneity can present itself in many ways. For example, many different combinations of mutations on different genes can elicit the disease. Also, the same gene may have a wide range of mutations that manifest differently.

Evolution

The frequency of alleles found in the population reflects evolutionary forces acting upon the population. Complex diseases that are under the influence of genetic heterogeneity have a genetic architecture that also reflects the evolutionary forces acting upon it. The genetic architecture of a disease refers to the number of relevant susceptibility genes, the frequency of these genes in the population, etc. For every generation, variants affecting diseases must resist the pressures of natural selection to maintain their presence in the population. For example, alleles associated with Alzheimer’s Disease may be commonly found in the population because the effect of the allele is only relevant in the later stages of life, where it no longer affects the individual's ability to reproduce.

Methods of Analysis

Variations in inheritance patterns, genetic penetrance and environmental influences complicate the process of uncovering genes in complex diseases. Whole genome and exome sequencing are techniques commonly used to sequence DNA needed to analyze variants potentially associated with specific diseases. Linkage analysis and genome-wide association studies are common genetic association studies performed on these sequences to provide additional information in identifying variants correlated with genetically heterogeneous diseases. These association studies have suggested the presence of modifier and susceptibility genes. Modifier genes are genes that affect the clinical presentation of diseases without actually contributing to its onset. In contrast, susceptibility genes are genes that contribute to the increased risk of developing a specific disease. Comparing the genetic makeup of biologically related members in a family study is also used to examine variants and genes that may be associated with the development of diseases. The segregation of variants between affected and non-affected relatives is analyzed in correlation to disease manifestation in the family.

Clinical Disorders

Cancer

Genomic instability involving point mutations, deletions, insertions, chromosomal translocations, and amplifications give rise to genetic heterogeneity in cancer. Genetic heterogeneity between different tumour types and within the same tumours results in great genetic diversity among cancers. Cancers with greater genetic heterogeneity are less likely to respond to long-term targeted treatment.

Schizophrenia

Schizophrenia is often characterized through clinical heterogeneity, presenting a wide variety of symptoms. This may be due to the extensive genetic heterogeneity associated with this disorder. Some genes may influence only susceptibility to this disorder while others influence only clinical presentation. Many variants identified include both common and rare mutations of single nucleotide polymorphisms, copy number variations, and de novo mutations. Large structural mutations at chromosomes 1q21.1, 15q13.3, 16p13.1, and 22q11.2 have been implicated in many independent and unrelated cases. Some of these genes have also been implicated in bipolar disorder, major depressive disorder, Autism, and attention deficit hyperactivity disorder.

Autism

In Autism, its etiology involves many rare point mutations, deletions, duplications, and larger chromosomal abnormalities. Additionally, it is characterized by a high rate of large de novo deletions and duplications. Rare and severe mutations in multiple genes important for brain development, including NRXN1, CNTN4, CNTNAP2, NLGN4, DPP10, and SHANK3 have been identified.