Methods to map quantitative trait loci (QTL) for age-at-onset traits


The University of Edinburgh



Supervisor: Dr. Peter Visscher (Institute of Cell, Animal and Population
Biology, University of Edinburgh,
http://www.icapb.ed.ac.uk/people/visscher.html)

 Funding: MRC Bioinformatics Research Studentship, from October 2003



The projects is suited to candidates with a background in the biosciences or
maths/stats, with a proven aptitude for numerical skills. For details on the
application procedure and for informal inquiries, contact
[log in to unmask]



The aim of the research is to develop and apply novel statistical methods to
genetically analyse age-at-onset (AAO) data in human populations, and to map
quantitative trait loci (QTL) affecting the AAO of psychiatric disorders in
complex pedigrees.  The purpose of such analyses is to quantify the amount
of genetic variation that exists in populations for AAO, and to locate
genome regions which contain genes affecting the AAO of a disease or other
trait. The developed methods will be applied to data on psychiatric
disorders in complex pedigrees through collaboration with Prof. Douglas
Blackwood (University of Edinburgh).



The hypothesis to be tested is that the new methods are more powerful in
dissecting genetic variation underlying AAO traits than existing methods,
and that they will help to lead to the identification of genetic loci
underlying the onset of complex human diseases. Existing statistical methods
for linkage and association of AAO and genetic markers  have drawbacks,
because they do not use the information efficiently by ignoring the nature
of the censored records. We propose to develop and apply survival analysis
methodology to model AAO directly, and to estimate polygenic and QTL
variance components for this trait, using pedigree information and genetic
marker data.



The workplan consists of



(i)              Applying existing survival analysis methods to existing
data on AAO of bipolar disorder and schizophrenia, in order to estimate the
amount of genetic variation for AAO in these traits and to identify and
estimate the effect of risk factors such as sex, cohort effects and
generation

(ii)                Developing methods to incorporate marker data, using
variance component methodology

(iii)               Monte Carlo simulation to test the power and accuracy of
the developed methods, and to compare the statistical power of the new
methods with that of existing methodology

(iv)              Application of developed methods to map QTL for AAO in
psychiatric disorders



Specialist training can be provided through the MSc course in Quantitative
Genetics and Genome Analysis
(http://www.gradlife.ed.ac.uk/msc_quan/msc_quan.htm) which run in the
department.





References

George, A.W., Visscher, P.M. and Haley, C.S. (2000) Mapping quantitative
trait loci in complex pedigrees: A two step variance component approach.
Genetics, 156:2081-2092.

Visscher et al., (2001). Genetic Survival Analysis of Age-at-Onset of
Bipolar Disorder. Evidence for Anticipation and a Year-of-Birth Effect in
Families. Psychiatric Genetics 11: 129-137.









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Peter M. Visscher
Institute of Cell, Animal and Population Biology
University of Edinburgh
West Mains Road
Edinburgh EH9 3JT
UK
tel.  +44 131 650 7702
fax. +44 131 650 6564
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