Saguenay Youth Study: a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health

Abstract

This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents.

Keywords: Addiction; Adolescence; Brain; MRI; Mental health; Middle age.

Fig. 1

Ranges of onset age (top) and years lived with disability (bottom) for common psychiatric disorders. Top figure adapted from (Paus et al., 2008a). Bottom figure based on data from (Whiteford et al., 2013). Percentages indicate proportion of years lived with disability explained by each mental and substance use disorder group in 2010 (100% = all psychiatric disorders).

Fig. 2

Associations between maternal behavior (licking and grooming), expression of the glucocorticoid receptor in the hippocampus, regulation of the hypothalamus-pituitary-adrenal axis and psychopathology (right side). From (Zhang et al., 2013). LG, licking and grooming; ACTH, adrenocorticotropin; CRF, corticotropin releasing factor; 5-HT, serotonin; camp, cyclic adenosine monophosphate; PKA, protein kinase A; NGFI-A, nerve growth factor-inducible factor A; CBP, CREB-binding protein; GR, glucocorticoid receptor.

Fig. 3

Transactions across organs: from eating behavior, through fat cells to cardiovascular regulation. Based on (Pausova, 2006). From (Paus, 2013). HFD, high-fat diet; FFA, free fatty acids; AGT, angiotensinogen; TNFα, tumor necrosis factor alpha; IL-6, interleukin 6; ROS, reactive oxygen species; RAAS, rennin-angiotensin-aldosterone system.

Fig. 4

Shaping the child's brain. This schematic diagram illustrates how parents’ brains contribute to the variations in their children's environments – internal (e.g., nutrition), physical (e.g., pollution, noise, access to parks) and social (neighborhood safety, school friends and role models).

Fig. 5

Risk/resilience profiling: virtual validation (dashed lines) and prognosis by ancestor/pedigree (solid lines). The numbers indicate hypothesized discriminative accuracy (0.5 = chance, 1 = perfect discrimination).

Fig. 6

Age-adjusted values (Mean ± SE) of brain volume (top), total cortical area (middle) and cortical folding (bottom) in female adolescents exposed (left column) and not exposed (right column) to maternal cigarette smoking during pregnancy, all plotted as a function of the KCTD8 genotype (rs716890; GG, GT and TT genotypes; G, guanine; T, thymine). The amount of variance (r²) explained by the genotype and statistical significance of the genotype effect of each phenotype are indicated. Note that we observed significant interaction between the KCTD8 genotype (rs716890) and “exposure” on total cortical area and cortical folding but not on brain volume.