Differentiating genetic and gene-environment interaction profiles of physical and mental health disorders.

Genetic risk and genetic vulnerability are different questions

Why do adverse childhood experiences have more serious health consequences for some people than for others? Genetics may help explain these differences, but finding the genetic variants that increase vulnerability to such early experiences requires asking the right question.

Two ways of asking about genes. A genome-wide association study, or GWAS, searches for SNPs: differences at individual positions in the DNA sequence that are associated with disease across a population. A genome-wide environment interaction study, or GWEIS, asks whether a variant’s association with disease changes according to a person’s experience. That dependence on experience is what scientists mean by an interaction. A variant could have little overall association with disease yet matter considerably among people exposed to adversity. Combining people with different experiences can obscure this relationship.

Comparing the approaches in the same population. The study examined 180,129 UK Biobank adults and four groups of hospital-recorded conditions: cardiovascular disease, type 2 diabetes, mood disorders, and neurotic or stress-related disorders. Childhood adversity was represented by a questionnaire item asking about feeling hated or unloved as a child. Of the participants, 22,372 reported this experience. The researchers compared the genetic signals from conventional association analyses with those from analyses that explicitly included an interaction with adversity.

The signals pointed to different variants. The two approaches did not identify overlapping SNPs at the study’s comparison threshold. This supports a distinction between genetic associations with disease in the population and genetic differences in responsiveness to an early experience. It also helps explain why a genetic risk score built from conventional GWAS findings may miss part of the biology of vulnerability.

The interaction findings remain suggestive and need confirmation in other samples. The study does not establish two completely separate sets of disease genes and adversity genes. It shows that the question asked in a genetic analysis determines which relationships can be detected, and that understanding vulnerability requires examining genetics together with experience.