br Methods br Results br Discussion br Conclusions br

Methods
Results
Discussion
Conclusions
Conflict of interest
Acknowledgements The authors gratefully acknowledge the participation of healthy young volunteers in this Tubacin cost study. The authors of this study are funded by grants from the NIHR (LM: Academic Clinical Fellowship), the MRC (Grant no. G1100402) (AG: Clinical Training Research Fellowship) and the Royal Society (SJB: University Research Fellowship). The authors express gratitude to Emily Garrett and Ashok Sakhardande for their time and help with recruitment and participant testing during the study.
Introduction The last century witnessed a dramatic growth in life expectancy. In the Unites States of America, life expectancy increased from an average of 44.8/47.8 (men/women) years in 1900 to an average of 73.9/79.4 years in 1998 (Smith and Bradshaw, 2006), owing mainly to the development of treatments of infectious diseases and the management of cardiovascular disorders and cancers (Guyer et al., 2000). Unfortunately, this increase in life expectancy has not been paralleled by increases in healthy life expectancy, defined as years lived without a disability. In 2002, the global (194 countries) gap between life expectancy and health-adjusted life expectancy was 7.5 years (Mathers et al., 2004). In developed countries, the main causes of Years Lived with Disability (YLD) – a metric used to calculate health-adjusted life expectancy – are non-communicable diseases (86.2% of all causes), with psychiatric conditions contributing the most (41.9%) to the overall health burden (Mathers et al., 2004). Among the latter conditions, unipolar depressive disorder (15%), alcohol abuse (6.8%) and Alzheimer\'s disease and other dementias (4.2%) stand out as the major causes of YLD. Although the increased prevalence of dementias is in part a reflection of longer life span, a cumulative impact of poor cardio-metabolic health on brain health is also one of the key mechanistic pathways leading to dementia (see below). One of the main reasons for the high health-burden associated with psychiatric disorders, such as depression and substance use, but also schizophrenia (2.3%) and bipolar disorder (2.2%), is their early onset and chronic course, resulting in a large accumulation of YLD over time (Fig. 1). For this reason, our quest to understand the causes and pathways leading to psychiatric disorders must take a developmental perspective. This perspective acknowledges the complexity of developmental cascades – and ensuing transactions – playing out over time, across levels and between organs (Masten and Cicchetti, 2010). In the following text, we will review briefly these three elements of developmental cascades in order to provide context for the design of the Saguenay Youth Study (SYS). We will conclude this section by providing motivation for expanding the SYS to include a multi-generational arm.
Saguenay Youth Study: overall design The first wave of the SYS cohort (2003–2012) has focused on establishing a community-based sample of adolescents (12 to 18 years of age) in which to evaluate associations between the exposure to an adverse prenatal environment, brain development and cardio-metabolic health (Pausova et al., 2007). In keeping with the above principles of developmental cascades, the cohort was set up so that detailed information could be collected at different levels (behavioral, systemic, molecular) and organs (brain, adipose tissue, cardiovascular system, endocrine system). Over a period of 10 years, we have collected a rich dataset in 1029 adolescents from the Saguenay Lac Saint Jean region (Quebec, Canada). This region is the home of the largest population with a known genetic founder-effect in North America (De Braekeleer, 1991; De Braekeleer et al., 1998; Gradie et al., 1988; Grompe et al., 1994), making it particularly suitable for studies of complex traits.