Question

) In complex disorders, genetic susceptibility can be supported by:

a) twin studies and adoption studies

b) genome wide association studies

c) linkage analysis

d) whole exome or whole genome sequence studies

e) all of the above

Answer 1

Susceptibility to complex human diseases such as diabetes and ischaemic heart disease arises from the complex interaction of environmental and host genetic factors. Many human diseases are genetically complex. Genetic susceptibility in such complex diseases can be supported by

1) Twin studies an adoption studies: Monozygotic (identical) twins share the same DAN while dizygotic (fraternal) twins do not. Studies of these twins provide an estimate of the relative contributions of shared genes and environment to disease phenotypes. Carrier status for hepatitis B virus and the febrile response to Plasmodium falciparum will be similar in monozygotic twin pairs. Concordance rates for twins that are brought up together or separately is high in acquisition of Helicobacter pylori infection, despite the different environments.

Twin and adoption studies indicate unambiguous role for genetic factors in the development of complex neurodevelopmental disorders. In autism, there is an estimated heritability of 90%. However, the causative gene is not yet identified.

2) Genome-wide linkage and association studies: Linkage analysis is a statistical analysis to localize genes with respect to each other in the genome. It is based on recombination frequency. Linkage analysis maps a disease phenotype in relation to polymorphic markers. It is based on analysis of families and hence is ideal to observe large variations in genes. However, it is not much effective in detecting small-scale variations. They help to identify genes or genetic regions that are transmitted from mother to offspring. Linkage analysis has been successful to study susceptibility to Helicobacter pylori infection and leprosy.

Genome wide studies do not make any assumption of genes involved and hence can identify new genes.

In genome-wide association studies, the whole genome is studies by use of thousands of Snaps and detects more subtle genetic effects. Studies have used up to zero·5 million of the approximately 11 million estimated Snaps in the human genome. Genome-wide association studies have a high false discovery rate. genotyping of nearly 93 000 Snaps in the genome identified a region of chromosome 6 that is associated with myocardial infarction.

3) Whole Genome or whole genome sequence studies: Numerous processes involved in development of complex human disease, which are governed by different genes. Whole genome sequencing studies help in identifying the genetic susceptibility to these diseases. CGH array, SNP microarrays, exome sequencing, and whole genome sequencing can help identify candidate genes associated with different diseases. CGH arrays detect copy number of genes while SNP arrays will identify the SNP variations in different diseases. Hence, it is possible to identify different polymorphisms as well as increase in copy number in a single experiment. Large amount of information is generated from small sample size quickly. This data is processed by bioinformatics analysis. Exome sequencing involves selective enrichment of the coding regions across the genome, followed by sequencing. There is significant reduction in sequencing cost in this method. Next generation RNA and protein sequencing techniques are routinely employed to gain more information on candidate genes.

Right option is e. All of the above.