Whole-genome analyses of whole-brain data: working within an expanded search space

Large-scale comparisons of patients and healthy controls have unearthed genetic risk factors associated with a range of neurological and psychiatric illnesses. Meanwhile, brain imaging studies are increasing in size and scope, revealing disease and genetic effects on brain structure and function, and implicating neural pathways and causal mechanisms. With the advent of global neuroimaging consortia, imaging studies are now well powered to discover genetic variants that reliably affect the brain. Genetic analyses of brain measures from tens of thousands of people are being extended to test genetic associations with signals at millions of locations in the brain, and connectome-wide, genome-wide scans can jointly screen brain circuits and genomes; these analyses and others present new statistical challenges. There is a growing need for the community to establish and enforce standards in this developing field to ensure robust findings. Here we discuss how neuroimagers and geneticists have formed alliances to discover how genetic factors affect the brain. The field is rapidly advancing with ultra-high-resolution imaging and whole-genome sequencing. We recommend a rigorous approach to neuroimaging genomics that capitalizes on its recent successes and ensures the reliability of future discoveries.