Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SEGWAY (Study on Environmental and GenomeWide predictors of early structural brain Alterations in Young students)

Teaser

Mounting evidence suggests that early life factors have an important impact on the occurrence of late-life neurological diseases. From a public health perspective this is of particular relevance for dementia. With increasing longevity the number of persons affected by dementia...

Summary

Mounting evidence suggests that early life factors have an important impact on the occurrence of late-life neurological diseases. From a public health perspective this is of particular relevance for dementia. With increasing longevity the number of persons affected by dementia is increasing drastically, with no available preventive treatment, resulting in a major burden at the individual and socio-economic level. Converging evidence indicates that pathological processes likely begin many years before clinical diagnosis. Interestingly, measures of brain structure on magnetic resonance imaging (MRI) that were shown to be powerful determinants of dementia in older persons can already show subtle alterations in young and middle-aged adults. The SEGWAY project aims to: (i) explore the contribution of variations in the genetic make-up of individuals to structural brain measures in young adults in their early twenties participating in the i-Share study, the largest ongoing study on student’s health; (ii) take a lifetime perspective by examining the shared genetic contribution to alterations in brain structure in young adulthood (i-Share study) and late-life, among participants of a large French population-based study, aged 65 years and older (3C-Dijon study); (iii) explore whether the impact of genetic factors on brain changes is modulated by the exposure to vascular risk factors (hypertension, hypercholesterolemia, obesity, smoking…) with an established impact on brain aging; (iv) examine the clinical significance of genes associated with changes in brain structure by testing their association with cognitive performance in both age groups, and with dementia risk in older adults. Replication of our findings will be sought in the multigenerational Framingham Heart Study and other independent studies. Identifying common biological mechanisms underlying both early and late-life structural brain changes would provide important information on the mechanisms and time-course of brain aging throughout a lifetime and could be of major importance for identifying novel drug targets and characterizing high risk populations most likely to benefit from early preventative interventions.

Work performed

During the first 18 months, 2,000 i-Share students have been recruited for the project, of whom over 93% have already undergone a brain MRI on a high resolution 3 Tesla scanner, and provided blood samples for the genetic analyses (the few remaining exams are scheduled after the student summer break). Numerous quantitative measures of brain structure are currently being generated, some of which are already available in a pilot subsample. We expect that the planned phenotypes will be generated on schedule by M24. An important component of this first period has been the management of incidental findings on brain MRIs conducted for the project (~2.5% of participants). We have established and applied a standardized protocol after extensive consultation of the i-Share ethics advisory board, as described in detail in the ethics report.

We had initially planned on genome-wide genotyping by M18. However, in order to increase the scientific impact at the same total cost, we have submitted an amendment, approved by the European Commission, to change some of the genomic methodologies for the project. This has postponed the process by a few months but will enable higher quality data. These changes arise from technological advances and substantial cost reductions for genome-wide genotyping and whole genome sequencing since the grant submission. First, we now propose to undertake genome-wide genotyping using the recently introduced Affymetrix UKBiobank Axiom array on the 2000 study participants, rather than an Illumina array as originally proposed, because of lower cost with equivalent coverage. Second, instead of targeted sequencing of two small genomic regions we propose to conduct whole genome sequencing, with 30X or more coverage, of 600 i-Share participants. This is made possible both by the reduced expenses for genome-wide genotyping (less costly array) and the recent cost reductions of whole genome sequencing technologies. It will enable high quality imputation of many millions of variants on all the participants, thus increasing greatly the power of the study.

While these changes have slightly postponed the genetic analyses on the i-Share cohort, we have started working on several other tasks in anticipation, which will also enrich the forthcoming analyses on the i-Share cohort. First, we have conducted heritability analyses of MRI-markers of brain aging in the 3C-Dijon study, to measure the genetic contribution to these structural brain changes in older persons. These analyses will be expanded to the i-Share cohort as soon as the data becomes available. Second, we have expanded the search for novel genetic determinants of MRI-markers of brain aging in older community persons (in the 3C-Dijon study and in a collaborative setting); we will explore their relation with early structural brain changes in young adults. Third, we have explored the modulation of genetic associations with white matter hyperintensity volume (WMHV), a quantitative MRI-marker of vascular brain aging, by hypertension, in the 3C-Dijon study, and we are expanding this in a collaborative setting.
Finally, we have begun elaborating strategies for replication and expansion of our findings in independent cohorts and have established additional collaborations in this context.

Final results

Progress beyond the state of the art:
With this project we propose to create a unique database to identify genetic determinants of early structural brain alterations in young adults participating in the i-Share study. Moreover, leveraging extensive brain imaging and genomic resources in older community persons from the 3C-Dijon study, we plan to take an original “lifetime” perspective, by exploring shared genetic variation of structural brain alterations between young and old adults. Cutting edge image processing techniques, obtained on a dedicated 3T MRI scanner, are being implemented. We have introduced novel cutting edge MRI-markers in addition to those described in the submitted project (including dilated perivascular space burden, peak width of skeletonized mean diffusivity on diffusion tensor imaging). To analyze genetic variants associated with structural brain phenotypes we plan to utilize the recently introduced Affymetrix UK Biobank Axiom array (high-throughput genotyping technology) on the 2000 study participants, which enables extensive genomic coverage at reasonable cost. Imputation on the most recent reference panels will be performed according to the latest standards, which will allow inference of genotypes at >70M sites. We will also use cutting-edge whole genome sequencing (WGS), in 600 i-Share participants. WGS provides a comprehensive assessment of all coding and noncoding genetic variants, both common and rare. Importantly, imputation quality for rare variants in the entire i-Share dataset will be substantially improved by incorporating WGS data from i-Share itself, in addition to reference genomes from other populations. The change from targeted sequencing to WGS is a major upgrade compared to the submitted project in terms of progress beyond the state of the art and expected potential impact. Novel statistical approaches will be implemented to enhance the discovery of genetic associations and explore pleiotropic genetic effects across the lifespan.

Expected potential impact:
There is a crucial need to improve our understanding of the genetic basis and temporal sequence that lead from structural brain changes in early adulthood to accelerated brain aging in late life, portending an increased risk of dementia. Indeed, no efficient strategies are currently available for the prevention of dementia, and identifying the molecular underpinnings of lifetime changes in brain structure could provide invaluable information to identify novel therapeutic targets and to detect populations at highest risk of accelerated brain aging and dementia who would be most likely to benefit from early, intensive interventions. The availability of extensive cognitive testing will also enable us to examine the clinical significance of genetic variants affecting brain structure, by testing their association with cognitive performance. Cognitive decline and dementia represent a major public health concern, and exploring their risk factors and mechanisms, including early structural brain changes that may potentially, later in life make the brain more vulnerable to neurodegenerative processes, is of the utmost importance at the community level.
Bringing genetic association findings into clinical use, e.g. for identification of drugable molecular targets, requires multiple additional steps, including identification of the causal variant(s) and gene(s). The initially planned targeted sequencing approaches have been replaced by whole exome sequencing, which will substantially expand our ability to fine-map genetic association signals. We have also planned detailed in silico bioinformatics annotation of identified association signals, using novel cutting edge tools, to follow-up on identified association signals and facilitate the subsequent design of more extensive functional experiments, for translation of genetic association findings into clinical use. These are regularly upgraded based on the latest progress in the field.

Final

Website & more info

More info: http://segwayproject.com.