S36 Invited Lectures

Session 2C. Gene Environment Interactions

2C-1 Approaches to evaluating gene-environment interactions

underlying DOHaD

C. Pennell *. School of Women’s and Infants’ Health, The University

of Western Australia, Perth, Australia

Recent studies have clearly established an inverse relationship be-

tween sub-optimal antenatal and postnatal environments, and the

development of adult diseases including the metabolic syndrome

(coronary heart disease, hypertension, stroke, insulin resistance,

type II diabetes and dyslipidemia), obesity, neurologic disorders

and mental illness. These observations have been confirmed in

multiple human populations and in numerous animal studies

in multiple species. Although adverse antenatal and postnatal

environments increase the risk of particular adult diseases, not

all individuals exposed to these environments develop these

conditions, suggesting that an individual’s genotype may contribute

to the eventual outcome. It has therefore been suggested that

gene-environment interactions underlie the developmental origins

of health and disease (DOHAD). This is illustrated by the influence

of polymorphisms in the peroxisome proliferator-activated receptor

(PPAR)-g2 gene on the relationship between size at birth and

adult diseases including: (1) insulin sensitivity and metabolism,

(2) hypertension, (3) obesity and (4) dyslipidemia. Similarly,

polymorphisms in the glucocorticoid receptor, a key control

element in the HPA axis, have been implicated in determining

obesity, hypertension, hypercholesterolemia and responses to

psychosocial stress in adults. Thus complex interactions between

genes and the environment modulate developmental programming

of adult disease.

With the development of new technologies capable of probing

the genome, exciting possibilities now present themselves to gain

new insight into gene-environment interactions underlying DOHaD.

When considering performing these studies, four specific areas

need to be considered including: (1) phenotypic criteria, (2) study

design, (3) considerations in the selection of control populations,

and (4) candidate gene selection. Each of these four areas will be

discussed in this presentation.

2C-2 Human genome epidemiology, biobanks, and DOHaD

L.J. Palmer*. Western Australian Institute for Medical Research

and University of Western Australia, Perth, Australia

E-mail: lyle@cyllene.uwa.edu.au

Common, chronic diseases continue to rise in incidence across

all age groups and their diagnosis, prevention, and treatment

continue to increase in complexity. Concomitantly, debates over

effective resource utilization in the Australian and other health

systems are becoming more common. New diagnostic, therapeutic,

interventional, and health promotion strategies are urgently

needed given our ageing populations.

A small but increasing number of genes and modifiable envi-

ronmental factors associated with complex diseases have been

discovered. The escalating utilization of genomic data in clinical,

epidemiological and public health investigations in novel and

creative ways represents fresh hope for disciplines beleaguered by

the potential for reverse causality, confounding and many forms of

bias.

It has become increasingly clear that there is a critical need

in DOHaD research for large, well-characterized, population-

based resources particularly longitudinal birth cohorts. The

development of such resources for the joint investigation of

environmental and genetic hypotheses is a key advance for

the growing integration of epidemiology with genetics and for

personalized medicine to become a public health reality. Numerous

population-based studies that include DNA banking are currently

ongoing around the world, or have been completed in the last

10 years. New large, national cohorts such as the MRC/Wellcome

Trust UK Biobank have been funded, with planned or ongoing

initiatives for national cohorts in a number of countries in

Western Europe, Scandinavia, North America and Australasia. These

exceptional cohort resources are another step on the long road to

discovering and utilizing the genes and modifiable environmental

factors underlying common human diseases.

Correspondence: Professor Lyle J Palmer, Western Australian

Institute for Medical Research, SCGH Campus, Ground Floor, B

Block, QE-II Medical Centre, Hospital Avenue, Nedlands Western

Australia 6009, Australia. Phone: +61 8 9346 1061; fax: +61 8 9346

1818.

2C-3 Gene early environment interaction and the metabolic

syndrome

J.G. Eriksson*. University of Helsinki and National Public Health

Institute, Helsinki, Finland

E-mail: Johan.Eriksson@helsinki.fi

Non-optimal growth during fetal life and infancy has been associ-

ated with a large number on non-communicable diseases including

the metabolic syndrome, type 2 diabetes and cardiovascular

diseases. Genetic factors are major players in the field of the

metabolic syndrome and type 2 diabetes and a large number of

strong candidate genes have been identified including the more

recently identified ones like TCF7L2, IGFBP-2 and CDKAL1.

We have previously reported interactions between intrauterine

growth and genes in relation to adult health outcomes based upon

findings from the Helsinki Birth Cohort Study. We have shown that

the effects of the Pro12Pro and Pro12Ala polymorphisms of the

PPARg2 gene depended on body size at birth. Those individuals

who had a small body size at birth and were carriers of the

Ala allele seemed to be protected against insulin resistance and

type 2 diabetes in later life. Similar findings have been reported

in relation to the PC-1 gene. These findings reflect gene-early

environment interactions and can be attributed to the phenomenon

of developmental plasticity.

In this report we will focus upon more recently identified candidate

genes and report on interactions between fetal growth and

genotype as well as on childhood growth and genotype.

Session 2D. The Offspring of Women with Severe

Mental Disorder

2D-1 Adverse pregnancy outcomes in mothers with

schizophrenia: maternal and paternal influences

C.M. Hultman*, P. Lichtenstein, S. Cnattingius, E. Nilsson.

Department of Medical Epidemiology and Biostatistics, Karolinska

Institutet, Stockholm, Sweden

Women with schizophrenia have an increased risk for adverse preg-

nancy outcomes. The mechanisms underlying these associations

are still unclear and maternal, paternal and/or common genetic

factors might influence the association. First, the increased risk

for adverse pregnancy outcomes among women with schizophrenia

might be explained by maternal behaviour (maternal factors)

during pregnancy, such as smoking or low education status. We

have shown that the increased risk for low birth weight among

off-spring to women with schizophrenia decreased from 80% to

30% when maternal factors, such as smoking, low education and

single motherhood, were controlled for. Nevertheless, an increased

risk for low birth weight remained even after these covariates

were controlled for. Secondly, fathers may also contribute to the

association, for example by creating non-optimal social and/or

economical circumstances in the family (paternal/parental factor).

Lastly, the association could be explained by genetic factors. The

risk for adverse pregnancy outcomes among offspring to fathers

with schizophrenia is mainly unknown.

By record linkage including two million births using Swedish

population-based registers, we have investigated the mechanisms

underlying the association between schizophrenia in the parents

Invited Lectures S37

and four adverse pregnancy outcomes. Schizophrenia in both

fathers and mothers seems to confer a risk for infant death.

By using information on parental full and half-siblings with and

without schizophrenia, possible genetic mediation was studied. The

association between schizophrenia and the increased risk for infant

death seems primarily to be explained by parental factors.

2D-2 Linking schizophrenia epidemiology and developmental

neurobiology; the impact of low prenatal vitamin D on

brain development

J.J. McGrath*. Queensland Centre for Mental Health Research,

University of Queensland, Australia

E-mail: john_mcgrath@qcmhr.uq.edu.au

Individuals born in winter and spring have a small but significantly

increase risk of later developing schizophrenia. While this finding

has been replicated countless times over the last eighty years,

the seasonally-fluctuating risk factor underlying the winter/spring

excess have been a mystery. Based on the season of birth effect

and other clues from epidemiology, we hypothesized that low

prenatal vitamin D may be a risk factor for schizophrenia. This

talk summarizes the epidemiological studies that have directly

or indirectly explored this hypothesis. Until recently, there has

been an absence of data exploring the role of vitamin D

during brain development. Over the last seven years our group

has compiled evidence from human studies and rodent models

that confirms the biological plausibility of this exposure with

respect to neurobiological outcomes. In particular, developmental

vitamin D deficiency in the rat and mouse is associated with

a behavioural phenotype which is informative for schizophrenia

research (e.g. enlarged cerebral ventricles, increased locomotion

after amphetamine etc). While the evidence linking low prenatal

vitamin D to schizophrenia is still inconclusive, animal experiments

have shown conclusively that low prenatal vitamin D impacts

adversely on the development of the rodent brain. Because

hypovitaminosis D is prevalent in pregnant women, this research

may have important public health implications.

2D-3 The neurodevelopmental hypothesis and schizophrenia.

Evidence from the Western Australian study of women

with severe mental illness

V. Morgan*, S. Zubrick, C. Bower, M. Croft, G. Valuri, A. Jablensky.

Neuropsychiatric Epidemiology Research Unit, School of Psychiatry

and Clinical Neurosciences, University of Western Australia,

Australia

In the neurodevelopmental model of schizophrenia, it is proposed

that disruption of normal development of the central nervous

system in utero or early infancy may manifest itself in adulthood

as schizophrenia, as well as giving rise to deficits in cognitive

and neurological functioning in childhood and early adolescence.

Disruption may be of genetic and/or environmental origin, with

obstetric complications one putative environmental risk factor.

Our study of a cohort of children of women with schizophrenia,

already at genetically high risk for developing the disorder

themselves, is designed to untangle genetic and environmental

contributions to their risk for schizophrenia and other adverse

outcomes. Using record linkage across several Western Australian

whole-of-population health databases including the midwives and

the psychiatric case registers, we identified 3174 high risk children

born 1980 1992 to all mothers on the psychiatric case register

with severe mental illness (schizophrenia, bipolar disorder, major

unipolar depression) and a comparison group of children born to

mothers with no psychiatric history. Fathers were identified using

birth registrations. Full psychiatric histories for mothers, fathers

and children were extracted, and data collected on obstetric

complications and other childhood morbidities.

This talk will examine both the risk of aetiologically plausible

indicators of neurodevelopmental insults such as neonatal

encephalopathy and low birthweight in the children of women

with severe mental illness, and assess the extent to which these

obstetric complications act independently of or interact with

genetic vulnerability to increase the risk of schizophrenia. The

specificity of findings to schizophrenia will be considered.

Session 2E. Muscle and Bone

2E-2 The developmental origins of ageing muscle:

consequences for metabolic and mechanical function

A.A. Sayer *. Southampton, UK

Muscle is key to human metabolic and mechanical function. Loss

of muscle mass and strength with ageing is called sarcopenia

and there is growing interest in its aetiology. Most research to

date has focused on the effect of genetic factors and adult

lifestyle on the loss of muscle in later life and there have

been few studies investigating influences operating earlier in

life. However epidemiological findings from birth cohorts such

as the Hertfordshire Cohort Study suggest that developmental

influences have important long-term consequences for human

muscle in terms of both mechanical and metabolic function. Thus

small size at birth is associated with lower grip strength, lower

non-fat mass and impaired glucose tolerance in older people.

Furthermore new evidence suggests that muscle strength and

glucose tolerance are directly related. The next stage of this

research is to identify the mechanisms underlying the link between

early growth, development and ageing of muscle using animal

models and detailed human physiological studies. The findings will

inform the development of effective interventions to minimise

muscle ageing and its adverse consequences in older people.

2E-3 Developmental and lifetime social influences on physical

capability and body composition in later life

G. Mishra, R. Cooper, M. Richards, R. Hardy, D. Kuh*. London,

UK

Tests of physical capability are summary markers of biological

ageing processes associated with quality of life, ability to carry out

everyday tasks, and subsequent frailty and death. They represent

a final common pathway for the effects of diseases of differing

severities and impact, many of which have developmental origins.

However, epidemiological studies have concentrated on adult risk

factors that may impair physical capability or explain covariation

in age-related decline in physical and cognitive capabilities. The

developmental origins of later life physical capability has been

studied less, although growing evidence links early growth to

adult lean mass and muscle function. Studies of the effects

of later childhood growth or of other developmental factors

on physical capability are rare. One exception is British cohort

study that has measures of physical capability at age 53 years

on 3000 men and women and prospective data since their

birth in March 1946. We report how childhood indicators of

muscle and cognitive development and socio-economic conditions

are associated with midlife grip strength, standing balance and

chair rising, independent of later risk factors. New measures

of body composition are currently being collected on this

cohort at 60 62 years, and will be used to investigate possible

mediating mechanisms. Our findings, set in the context of other

epidemiological evidence, suggest that the prevention of frailty

needs to start early in life and that the common cause hypothesis

should be extended to include developmental processes that shape

initial differences in physical and cognitive capabilities.