Diagnosing migraine from genome-wide genotype data: a machine learning analysis

Abstract Migraine has an assumed polygenic basis, but the genetic risk variants identified in genome-wide association studies only explain a proportion of the heritability. We aimed to develop machine learning models, capturing non-additive and interactive effects, to address the missing heritability. This was a cross-sectional population-based study of participants in the second and third Trøndelag Health Study. Individuals underwent genome-wide genotyping and were phenotyped based on validated modified criteria of the International Classification of Headache Disorders. Four datasets of increasing number of genetic variants were created using different thresholds of linkage disequilibrium and univariate genome-wide associated p-values. A series of machine learning and deep learning methods were optimized and evaluated. The genotype tools PLINK and LDPred2 were used for polygenic risk scoring. Models were trained on a partition of the dataset and tested in a hold-out set. The area under the receiver operating characteristics curve was used as the primary scoring metric. Classification by machine learning was statistically compared to that of polygenic risk scoring. Finally, we explored the biological functions of the variants unique to the machine learning approach. 43,197 individuals (51% women), with a mean age of 54.6 years, were included in the modelling. A light gradient boosting machine performed best for the three smallest datasets (108, 7,771 and 7,840 variants), all with hold-out test set area under curve at 0.63. A multinomial naïve Bayes model performed best in the largest dataset (140,467 variants) with a hold-out test set area under curve of 0.62. The models were statistically significantly superior to polygenic risk scoring (area under curve 0.52 to 0.59) for all the datasets (p<0.001 to p=0.02). Machine learning identified many of the same genes and pathways identified in genome-wide association studies, but also several unique pathways, mainly related to signal transduction and neurological function. Interestingly, pathways related to botulinum toxins, and pathways related to the calcitonin gene-related peptide receptor also emerged. This study suggests that migraine may follow a non-additive and interactive genetic causal structure, potentially best captured by complex machine learning models. Such structure may be concealed where the data dimensionality (high number of genetic variants) is insufficiently supported by the scale of available data, leaving a misleading impression of purely additive effects. Future machine learning models using substantially larger sample sizes could harness both the additive and the interactive effects, enhancing precision and offering deeper understanding of genetic interactions underlying migraine.