Homozygosity, inbreeding and health in European populations
View/ Open
McQuillan2009.doc (5.455Mb)
Date
14/10/2009Author
McQuillan, Ruth
Metadata
Abstract
Inbreeding results in increased levels of homozygosity for deleterious recessive
alleles, leading to increased incidence of monogenic disease in inbred families. It
has also been suggested that inbreeding increases the risk of diseases such as cancer
and heart disease, implying a role for the combined effects of many recessive alleles
distributed across the genome. A better understanding of the links between
inbreeding, homozygosity and disease is therefore of interest to those concerned with
understanding the genetic architecture of complex disease. A homozygous genotype
is defined as autozygous if both alleles originate from the same ancestor.
Quantifying inbreeding involves quantifying autozygosity. A new, observational
method of quantifying autozygosity using genomic data is developed here. Based on
runs of homozygosity (ROH), this approach has a sound theoretical basis in the
biological processes involved in inbreeding. It is also backed by strong empirical
evidence, correlating strongly with pedigree-derived estimates of inbreeding and
discriminating well between populations with different demographic histories. ROH
are a signature of autozygosity, but not necessarily autozygosity of recent origin.
Short ROH are shown to be abundant in demonstrably outbred individuals and it is
suggested that this is a source of individual genetic variation which merits
investigation as a disease risk factor, although denser genotype scans than those used
in the present study are required for the reliable detection of very short ROH. In the
absence of such dense scans, it is suggested that ROH longer than 1 or 1.5 Mb be
used to estimate the effects of inbreeding on disease or quantitative physiological
traits (QT), and that a simple measure of homozygosity be used to investigate overall
recessive effects. Evidence for recessive effects on 13 QT important in cardiovascular and metabolic disease was investigated in 5 European isolate
populations, characterised by heightened levels of inbreeding. A significant decrease
in height was associated both with increased homozygosity and (to a lesser extent)
with increased ROH longer than 5 Mb (i.e. inbreeding) estimated using a 300,000
SNP panel. No evidence was found for recessive effects on any of the other QTs.
Evidence for recessive effects on colorectal cancer risk were investigated in two
outbred case control samples typed with a 500,000 SNP panel. Cases were
significantly more homozygous and had more of their genome in short ROH than did
controls. Cases were significantly more homozygous than controls even when inbred
individuals were removed from the sample. There was also some evidence of an
inbreeding effect, with inbred subjects having slightly significantly higher odds of
colorectal cancer than outbred subjects. This study provides evidence of recessive
effects on a common, complex disease in outbred populations and on height in both
inbred and outbred populations and shows that such effects are not solely attributable
to increased levels of homozygosity resulting from recent inbreeding. Individual
variation among outbred individuals in the proportion of the genome that is
homozygous may be important in disease risk. The development of denser genotype
scans will facilitate better enumeration of short ROH in outbred individuals so that
these can be properly enumerated and investigated as a disease risk factor.