rs1003194 — CALCA/CALCB

CALCA/CALCB — The CGRP Gene Locus and Migraine Susceptibility

Calcitonin gene-related peptide (CGRP) is the central molecular mediator of migraine headache. During a migraine attack, trigeminal neurons release CGRP into the meningeal vasculature, producing the intense throbbing pain, vasodilation, and neurogenic inflammation that define the condition. CGRP is encoded by two closely related genes on chromosome 11: CALCA¹¹ CALCA
encodes alpha-CGRP, the dominant isoform in peripheral trigeminal neurons and the primary CGRP source during migraine and CALCB²² CALCB
encodes beta-CGRP, expressed in enteric and sensory neurons and the locus containing the cis-eQTL at rs1003194. rs1003194 sits approximately 26 kilobases downstream of CALCB in an intergenic regulatory region — making it, as of 2022, the first genome-wide significant migraine risk variant to directly implicate the CGRP gene region itself.

The clinical significance of this locus goes beyond epidemiology. CGRP is the molecular target of the entire newest generation of migraine preventive and acute therapies: four anti-CGRP monoclonal antibodies approved for migraine prevention (erenumab, fremanezumab, galcanezumab, eptinezumab) and three gepant small-molecule CGRP receptor antagonists approved for acute or preventive treatment (rimegepant, ubrogepant, atogepant). Carrying genetic variants at the CGRP gene locus itself — variants that alter CALCB gene expression — places you at the intersection of migraine susceptibility genetics and the drugs designed to correct that biology.

The Mechanism

rs1003194 is an intergenic variant with regulatory function: it acts as a cis-eQTL for CALCB³³ cis-eQTL for CALCB
a cis-eQTL variant influences expression of a nearby gene in the same chromosomal region; rs1003194 changes how much CALCB mRNA is produced. Fine-mapping using the FOCUS algorithm (Supplementary Table 11c of Hautakangas 2022) prioritizes CALCA, CALCB and INSC as the most likely causal genes at this locus. The biological mechanism is consistent with the known migraine pathophysiology: if the A allele at rs1003194 increases CALCB expression in sensory neurons, even a modest elevation in CGRP availability would lower the threshold for trigeminovascular activation and migraine onset. The locus is intergenic, so there is no amino acid change — this is a regulatory variant affecting how much CGRP the trigeminal nervous system can produce.

The Evidence

The primary evidence comes from Hautakangas et al. 2022⁴⁴ Hautakangas et al. 2022
Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nature Genetics 54:152–160, the largest migraine GWAS to date. The study analyzed 102,084 migraine cases against 771,257 controls, identifying 123 genome-wide significant loci, of which 86 were previously unknown. rs1003194 emerged as the lead SNP at the CALCA/CALCB locus with P = 2.43×10⁻¹⁰, passing the genome-wide significance threshold (P < 5×10⁻⁸) with nearly two orders of magnitude to spare. The authors describe this as "a convincing association at the chromosome 11 locus that contains the CALCA and CALCB genes encoding CGRP itself," explicitly distinguishing the strength of this signal from weaker associations at CGRP receptor genes in the same dataset.

The CALCA/CALCB locus was not classified as subtype-specific — it did not appear among the three aura-specific loci (HMOX2, CACNA1A, MPPED2) or the two migraine-without-aura loci (near SPINK2 and FECH), placing it in the broader migraine susceptibility category that elevates risk regardless of headache subtype.

Chasman et al. 2024⁵⁵ Chasman et al. 2024
Shared Genetics of Migraine and Gastrointestinal Disorders. Neurology Genetics identified the CALCA/CALCB locus as one of 22 genomic regions showing distinct local genetic sharing patterns between migraine and gastrointestinal conditions — with inverse sharing for GERD and peptic ulcer disease but concordant sharing for IBD and diverticular disease. This pleiotropy reflects CGRP's broad role in visceral pain signalling and mucosal inflammation beyond the trigeminal system.

On the therapeutic side, Bhakta et al. 2021⁶⁶ Bhakta et al. 2021
Migraine therapeutics differentially modulate the CGRP pathway. Cephalalgia characterised the distinct mechanisms of CGRP-targeted agents: anti-ligand antibodies (fremanezumab, galcanezumab) block only CGRP, while anti-receptor antibodies (erenumab) and gepants also block adrenomedullin and intermedin signalling at the canonical CGRP receptor. This mechanistic difference is clinically relevant for A-allele carriers: drugs targeting the CGRP ligand produced by CALCA/CALCB may have a direct pharmacological relationship to the elevated CGRP the locus may confer.

Practical Actions

For A-allele carriers, the clinically actionable implication is that the entire CGRP-targeted drug class — the most effective class of migraine preventives developed in the last 30 years — directly corrects the biology this locus influences. If you carry A alleles at rs1003194 and experience frequent migraine, your genetics provide an evidence-based rationale for discussing CGRP-targeted therapy with a neurologist. The eQTL evidence suggests the A allele alters CALCB expression, making anti-CGRP ligand therapies (fremanezumab, galcanezumab, eptinezumab) especially mechanistically aligned with this locus.

For GG individuals without the A allele: migraine susceptibility at this locus is at the lower end of the genetic range, though migraine is polygenic and over 120 other loci contribute independently.

Interactions

The CALCA/CALCB locus interacts biologically with the CGRP receptor gene complex (RAMP1, CALCRL). Variants in RAMP1 (rs7590387) have been reported in pharmacogenomics studies of erenumab response — RAMP1 encodes receptor activity-modifying protein 1, which partners with CALCRL to form the functional CGRP receptor that binds the peptide encoded at this locus. Together, CALCA/CALCB (ligand production) and RAMP1/CALCRL (receptor complex) form the complete CGRP axis; variants at both ends of this axis may compound to determine individual CGRP signalling tone.

The TRPM8 migraine locus (rs10166942) operates through a distinct cold-sensing/pain- threshold pathway and is independently additive with the CALCA/CALCB locus.