Drs Jim Wilson and Peter Joshi - 3 potential PhD projects
Emails:
jim.wilson@ed.ac.uk
Mitochondrial DNA and complex traits of public health importance
The application of genome-wide association studies (GWAS) has
revolutionised our understanding of the genetic susceptibility to complex
diseases. Over 2000 associations to disease end points or risk factors
have been reported over the last five years, many of which have led to
substantive insights into disease mechanism. However, there remain
significant parts of the genome which are not routinely assayed in GWA
studies, the most important of which might be the mitochondrial DNA. The
mtDNA is only 16.5 kb in length but encodes certain critical components
of the mitochondrial oxidative phosphorylation complexes and mutations
are known to cause a number of genetic diseases. The development of a
custom-designed exome chip, including over 300 mtDNA variants, and which
has been genotyped in over 1 million participants, provides the
opportunity to investigate whether mitochondrial variation influences
the risk of complex diseases of public health importance, such as
type-2-diabetes and cardiovascular disease. This project will extend our
existing large scale international collaborations (ROHgen, Ygen, KinGen)
to initiate mtGEN and assess the association of mitochondrial genetic
variation with 40 quantitative traits and risk factors for chronic disease
and estimate the matrilineal heritabilities in cohorts with deep
pedigrees.
The scope and mechanism of inbreeding depression in humans
It has long been known that cousin marriage increases the risk of Mendelian
diseases and birth defects but until recently it was unclear whether the
increased homozygosity in the offspring influenced their risk of complex
diseases like coronary artery disease, type-2-diabetes and chronic
obstructive pulmonary disease. Moreover, it was not known whether the
subtle differences in parental relationship common in most societies
today influenced risk. The availability of large scale genomic data from
hundreds of thousands of research subjects now allows us to investigate
these fundamental questions. This project will extend our survey of the
effects of genome-wide homozygosity to a large number of complex traits
of biomedical and evolutionary interest using the ROHgen consortium
of >100 cohort studies interested in homozygosity. Analysis of both long
and short runs of homozygosity and regional mapping of homozygous effects
will illuminate the mechanism of inbreeding depression and highlight
areas of the genome harbouring recessive variants influencing the study
traits.
The genetics of longevity
A new wave of increasingly large scale genetic information is being
produced by population cohorts internationally. This opens up novel
possibilities in understanding the contribution of genetic variation to
many human traits and diseases, in particular human lifespan, which has
hitherto been understudied due to lack of statistical power. This project
will focus on the analysis of evidence for genetic association with human
lifespan. Work will employ 500k subjects genotyped at UK Biobank and
population cohorts run by us and our collaborators (Generation Scotland,
ORCADES, EGCUT) to examine the genomic architecture of lifespan, to
estimate the heritability of living to different ages, to explore what
lifespan genetics have in common with chronic diseases and healthy ageing,
to explore novel association signals and to follow up confirmed signals
using bioinformatic analysis.