# 37 - C. Alternative approaches in genetic studies

# C. Alternative approaches in genetic studies

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Linkage vs. association 
Linkage studies 
Association studies 
Uses families 
Uses cases and controls or families with ‘internal controls’ 
Detectable over large distances >10cM 
Detectable only over small distances <1cM 
Can usually only detect large effects i.e. RR>2 
Capable of detecting small effects e.g. OR<2 
From McGuffin et al. (ed) Psychiatric genetics and genomics. Oxford Press: 2002 
C. Alternative approaches in genetic studies 
 Transgenic studies: Transgenesis is a term that describes the transfer of a gene from one species to 
another. In practice, this term often refers to the insertion of a modified mouse gene into the mouse 
genome to study gene function. Transgenesis is a direct and powerful approach for analysing gene 
function. 
 Epigenetics: A discrepancy exists between the information provided by the DNA sequence (i.e. 
number of genes) and what is translated and produced by cellular machinery (messenger RNA and 
proteins). Though the DNA sequence provides a blueprint for synthetic activities of the cell, a number 
of ‘epigenetic’ modifications occur resulting in a second, equally complex layer of information. 
Waddington coined the term epigenetics to explain such mechanisms. DNA methylation and histone 
modification explain most of the epigenetic variations discovered to date. Crow has argued for long 
that epigenetic defects explain most of the concordance seen in schizophrenia; according to Crow, the 
hemispheric laterality and language specialisation unique to human brains is the source of 
schizophrenic defect and it can be ascertained only by an epigenetic enquiry. 
 Position effects: gene activity can be dependent upon the precise chromosomal location of the gene 
and its ‘neighbourhood’. Such genes will show altered activity during translocation, even if the gene 
itself is not disrupted by chromosomal breakage. 
 Endophenotypes: This term was coined by Gottesman and Shields in 1975. An endophenotype is an 
unseen but measurable phenomenon that is present in the distal genotype to disease pathway. It can 
be a biochemical, neuroimaging, electrophysiological, pathological, neuropsychological or sociofunctional marker. To be termed as an endophenotype, Gottesman suggested certain criteria to be 
satisfied by an identified disease marker. These are as follows: 
1. Must be associated with a candidate gene or region 
2. Must be present with a high relative risk in relatives, thus cosegregating with actual illness 
3. Must be a parameter associated with disease with biological plausibility 
4. Must be independently expressed in clinical state (i.e. must not be a state but a trait marker) 
5. Must be heritable 
6. Must be present in relatives more often than general population 
It is anticipated that the genetics of a complex construct such as schizophrenia can be studied easily in 
more or less Mendelian fashion if the constructs are broken down to constituent endophenotypes. The 
simpler a construct under study, the less number of genes will be on the causal pathway. Working