The balance between heritable
and environmental aetiology of
Kari Hemminki, Justo Lorenzo Bermejo and Asta Försti
Abstract | The Human Genome Project and the ensuing International HapMap
Project were largely motivated by human health issues. But the distance from a
DNA sequence variation to a novel disease gene is considerable; for complex
diseases, closing this gap hinges on the premise that they arise mainly from
heritable causes. Using cancer as an example of complex disease, we examine
the scientific evidence for the hypothesis that human diseases result from
interactions between genetic variants and the environment.
The present flood of genetic and genomic
data and references to genomic medicine
might give the impression that “…most
diseases are the result of the interactions of
multiple genes and environmental factors…”1
or that “…almost all human diseases result
from interactions between genetic variants
and the environment.”2 However, these state-
ments do not seem to reflect that many stud-
ies point to a predominantly environmental
causation of complex diseases2–8, or the lim-
ited progress that is widely acknowledged in
the genetic analysis of common diseases6,9–11.
The main question that remains in human
disease genetics is that of aetiology: how
much do we understand about the heritable
and environmental causation?
Heritable causes of complex diseases
remain largely elusive, despite tremendous
efforts to understand them. Partly, this is
because the genes that underlie complex
diseases are thought to have weak effects
on disease susceptibility, conveying
familial clustering with complex non-
Mendelian patterns, which explains the
connotation ‘complex disease’. By contrast,
the genes that are identified often confer
a high risk of disease (high penetrance)
to carriers12,13. Technological excellence
in genomics does not automatically lead
to benefits in human health, which could
require a true understanding of the aetiol-
ogy of these ‘complex’ or ‘multifactorial’
diseases, and which, we argue, require
a true understanding of the role of the
Here we explore the magnitude of
complex-disease heritability and the role
of the environment in their aetiology. The
basic dilemma in complex-disease genomics
in the developed countries is that heritable
causes will be difficult to find, because envi-
ronmental factors have increased the back-
ground incidence to over 10 times the level
that is found in the developing countries4,6,15.
Moreover, the inferred gene–environment
interactions, that is, the expression of the
heritable factors against a high background
of environmentally dominated disease, are
The quest for aetiological understand-
ing is shared by all complex diseases16.
Here we use cancer as an example of a
complex disease to examine the heritable
and environmental aetiology. Our choice is
motivated by the existence of reasonably
uniform diagnostics, and the availability
of global incidence figures and a wealth of
aetiological and mechanistic data.
We use ‘genetic’ as defined in the
Dorland’s Illustrated Medical Dictionary,
meaning “…pertaining to or determined
by genes”, and ‘hereditary’ and ‘heritable’
meaning “…genetically transmitted from
parent to offspring.” Note that ‘genetic’
does not differentiate between the germ
line and the somatic origin, in contrast to
‘hereditary’ and ‘heritable’. ‘Heritability’ is
the phenotypic variance that is attributable
to genetic effects17. Heritability specifically
considers variation in the occurrence of
the disease or trait between individuals.
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© 2006 Nature Publishing Group
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Supported by Deutsche Krebshilfe, Swedish Cancer Society,
Swedish Council for Working Life and Social Research and
Competing interests statement
The authors declare no competing financial interests.
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
BRCA1 | BRCA2 | GSTM1 | GSTT1 | HRAS1 | MTHFR | NAT2 | TNFA
American Cancer Society Guidelines: http://www.cancer.
Connecticut Tumor Registry:
German Cancer Research Center Division of Molecular
Genetic Epidemiology homepage:
Human Genome Project: http://www.ornl.gov/sci/
International Agency for Research on Cancer:
National Institutes of Health: http://www.nih.gov
NIH Genes and Environment Initiative: http://www.gei.nih.gov
Swedish Cancer Registry:
UK Biobank: http://www.ukbiobank.ac.uk
Access to this links box is available online.
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