Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools

Abstract

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine's polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100-12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of 'pleiotropic' variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.

Keywords: bipolar disorder; depression; genetics; migraine; schizophrenia.

Figure 1

Conceptual figure illustrating MiXeR’s ability to characterise genetic overlap beyond genetic correlation adapted from Smeland et al. Four scenarios of genetic overlap (A–D) with corresponding MiXeR Venn diagrams and genetic correlations. Genetic overlap with a preponderance of shared variants with the same (A) or opposite (B) effect directions results in either positive (A, red bar) or negative (B, blue bar) genetic correlation. However, since genetic correlation provides an estimate of the correlation of effect sizes between two traits, it is unable to discriminate between scenarios C and D, both of which return minimal genetic correlations. In contrast, since MiXeR estimates the number of shared variants regardless of effect direction, MiXeR successfully estimates more extensive genetic overlap in D compared to C, represented by the larger shared component (grey).

Figure 2

Total number of shared and unique variants estimated to influence migraine and mental disorders. Results from the MiXeR analysis for migraine (MIG) and each of (A) bipolar disorder (BIP), (B) depression (DEP) and (C) schizophrenia (SCZ). Venn diagrams representing the unique and shared variants associated with migraine and each of bipolar disorder, depression and schizophrenia. Polygenic overlap is represented in a lighter shade, migraine in yellow, bipolar disorder in purple, depression in brown and schizophrenia in green. The numbers indicate the estimated number of variants in thousands per component with standard deviations in parentheses. The size of the circle reflects the extent of polygenicity for each disorder.

Figure 3

Chromosomal distribution of genetic loci jointly associated with migraine and mental disorders. Manhattan plots showing the −log₁₀ transformed conjunctional FDR values for (A) depression (DEP) and migraine (MIG) (orange) and (B) schizophrenia (SCZ) and migraine (blue) for each SNP (y-axis) against chromosomal position (x-axis). The dotted line represents the conjFDR threshold for significant association <0.05. Black outlined circles represent independent lead SNPs.

Figure 4

Spatiotemporal gene expression of all mapped genes. Dendrogram and heat map showing spatiotemporal gene expression of all mapped genes for (A) migraine (MIG) and depression (DEP) and (B) migraine and schizophrenia (SCZ) using RNA sequencing data from BrainSpan over 11 developmental periods (columns) and 16 brain regions (rows). Global expression of mapped genes for depression and migraine was low from the mid-foetal stage to early childhood, increasing from middle childhood to early adulthood with highest expression during early adulthood. Expression of mapped genes for schizophrenia and migraine was more distributed, with highest expression during the late foetal stage, early childhood and early adulthood. Highest expression of mapped genes for both migraine and depression and migraine and schizophrenia occurred in the primary auditory cortex (A1C) during early adulthood, during which there was also high expression in the primary sensory (S1C), primary motor (M1C), primary visual (V1C), inferior temporal (ITC), ventrolateral prefrontal (VFC), orbitofrontal cortices (OFC) and thalamus (THA) for both sets of genes. There was also high expression in the thalamus at several developmental stages from late foetal to early adulthood for schizophrenia and migraine, while expression in the thalamus increased steadily from the newborn stage to early adulthood for depression and migraine. Brain regions were clustered using unsupervised hierarchical cluster analysis. Gene expression is indicated from high (red) to low (blue). AMY = amygdala; CBC = cerebellum; DFC = dorsolateral prefrontal cortex; HIP = hippocampus; IPC = inferior parietal cortex; MFC = medial prefrontal cortex; STC = superior temporal cortex; STR = striatum. Refer to the Supplementary material for more details.