​Neuroimaging-genetic cohorts in general population bring together two types of data: brain imaging and genetic data. These are unique and valuable tools for discovering associations between genetic variants and characteristics derived from brain imaging (concept of endophenotypes*). They are also invaluable resources for studying the relative influence of genetics and environment on the variance of brain characteristics observed in normal and pathological populations. Analysis of such cohorts allows the search for genetic associations with earlier or more reliable characteristics than the classic binary phenotypes, such as diagnostics observable in an individual.

The UK Biobank general population cohort, which contained 16,304 subjects at the time of the study, is currently the best example in the world of the use that can be made of this type of tool. This cohort allowed the investigators to conduct a genome-wide haplotype analysis (sequences of multiple contiguous variants inherited from the same parent) for the opening value of 123 brain sulci (sulci are the elongated depressions observed on the surface of the cortex). A first originality of the work is that association studies are usually conducted for each individual genetic variant and, when haplotypic studies are conducted, they are performed on very limited portions of the genome, for reasons of computational burden. The second originality is the endophenotype analyzed, i.e. the opening of the sulci distributed throughout the cortex, which is an indicator of brain aging.

Using genetic maps, the researchers defined 119,548 low-recombination blocks distributed along the 22 autosomal chromosomes and analyzed 1,051,316 haplotypes. They thus confirmed the genetic particularity of the regulatory region of the KCNK2 gene located on chromosome 1 and its association with the opening of the sulci of the cingulate cortex. They also identified three additional genomic regions of interest (on chromosomes 9, 12, and 16), whose found association is independently replicated in approximately 5000 additional subjects.



Interior volumes of cortical sulci whose opening was studied. Colored sulci are those found associated with a haplotypic region of chromosome 1. Color code: level of significance of association.
© S Karkar, E Le Floch, V Frouin /CEA


This work has made it possible to map sulci that show variability in opening that can be partially explained by regions of the genome. They also allowed to compare the relative interests of classical association methods with the haplotypic approach chosen here, showing in particular that genome-wide haplotype analyses are more sensitive than SNP** (Single Nucleotide Polymorphism) approaches and represent an interesting and statistically robust alternative.

Contact : Vincent Frouin

* The concept of endophenotype was created to categorize complex, primarily mental, disorders into simpler, stable, intermediate manifestations accurately measured by neuroimaging, that have a proven genetic link to disease.

** SNPs (Single Nucleotide Polymorphism) are the most abundant form of genetic variation in the human genome. They account for more than 90% of all differences between individuals. It is a type of DNA polymorphism in which two chromosomes differ on a given segment by a single base pair.