# Family health history and pharmacogenomics show cross generation premature amitriptyline discontinuation is associated with CYP2C19 loss of-function enrichment

## TL;DR

The study shows that children with a family history of early amitriptyline discontinuation are more likely to have genetic variants affecting drug metabolism.

## Contribution

The study demonstrates that family health history can identify individuals enriched for pharmacogenomic variants affecting drug response.

## Key findings

- 13% of offspring prescriptions overlap with parental prescriptions, mostly short-term treatments.
- Offspring with two-generation histories of early amitriptyline discontinuation are enriched for CYP2C19 poor metabolizers.
- Parental discontinuation does not predict offspring discontinuation, but two-generation history does.

## Abstract

Genetics influence medication response yet integrating family health history (FHH) of medication response with pharmacogenomics remains underexplored. The objective of this study was to examine cross-generational medication exposure patterns and assess the utility of FHH for medication response using electronic health records.

Genes & Health (G&H) data from Bangladeshi and Pakistani participants were analysed for parent-offspring trios with medication exposure. Premature discontinuation of amitriptyline was defined as discontinuation within three months. Logistic regression and Fisher’s exact test explored the relationship between parental discontinuation, offspring discontinuation, and CYP2C19 loss-of-function variants.

13% of offspring prescriptions overlap with parental prescriptions, primarily short-term treatments (antibiotics, vaccines, steroids). In 96 trios, cross-generational amitriptyline exposure is observed. Parental discontinuation does not predict offspring discontinuation (p = 0.275, OR 1.70). However, offspring with two-generation histories of early discontinuation are significantly enriched for CYP2C19 predicted poor metabolizers (38% vs. 10.5%, p = 0.049, OR 4.86).

FHH of medication response can highlight individuals enriched for pharmacogenomic variants. This is a clinically useful finding, which may flag psychiatric patients with a two-generation history of early amitriptyline discontinuation or intolerance as a priority for pharmacogenomic testing. This study demonstrates the potential of integrating FHH into clinical pharmacogenomics for actionable insights.

It is routine medical practice to ask about family history of medical problems. Though we know that some risk of reacting badly to a medication is also inherited it is not common practice to look for clues in family history when deciding which medicine might be best suited for a patient. This study looked at how commonly participants were prescribed medication that a parent had been prescribed and found that 13% of medication prescribed to a child had also been prescribed to a parent. The commonly used antidepressant amitriptyline was prescribed to a child and a parent in 96 families within this study. The authors examined patterns of amitriptyline prescriptions to see if medication use was predictive of inherited characteristics known to impact on medication response. They found that a parent stopping the medication quickly did not predict that the child would also do so. However, in families where both the parent and the child stopped taking amitriptyline within 3 months, the children were nearly 5 times more likely to be slow amitriptyline metabolisers (predicted from DNA to break down the medicine slowly). This shows that using routine prescribing data from families can highlight offspring with high genetic risk of an atypical response to medication.

Magavern, Marengo et al. examine cross-generational medication exposure patterns and assess the utility of family health history for medication response using electronic health records. They find that offspring with two-generation histories of early amitriptyline discontinuation were significantly enriched for CYP2C19 predicted poor metabolizers.