Glucose phosphate isomerase deficiency demasked by whole-genome sequencing: a case report.

BACKGROUND: Glucose-6-phosphate isomerase deficiency is a rare genetic disorder causing hereditary nonspherocytic hemolytic anemia. It is the second most common glycolytic enzymopathy in red blood cells. About 90 cases are reported worldwide, with symptoms including chronic hemolytic anemia, jaundice, splenomegaly, gallstones, cholecystitis, and in severe cases, neurological impairments, hydrops fetalis, and neonatal death. CASE PRESENTATION: This paper details the case of the first Danish patient diagnosed with glucose-6-phosphate isomerase deficiency. The patient, a 27-year-old white female, suffered from lifelong anemia of unknown origin for decades. Diagnosis was established through whole-genome sequencing, which identified two GPI missense variants: the previously documented variant p.(Thr224Met) and a newly discovered variant p.(Tyr341Cys). The pathogenicity of these variants was verified enzymatically. CONCLUSIONS: Whole-genome sequencing stands as a potent tool for identifying hereditary anemias, ensuring optimal management strategies.

Pseudoneurotic Symptoms in the Schizophrenia Spectrum: A Longitudinal Study of Their Relation to Psychopathology and Clinical Outcomes.

BACKGROUND AND HYPOTHESIS: Nonpsychotic symptoms (depression, anxiety, obsessions, etc.) are frequent in schizophrenia-spectrum disorders and are usually conceptualized as comorbidity or transdiagnostic symptoms. However, in twentieth century foundational psychopathological literature, many nonpsychotic symptoms with specific phenomenology (here termed pseudoneurotic symptoms) were considered relatively typical of schizophrenia. In this prospective study, we investigated potential associations of pseudoneurotic symptoms with diagnostic status, functional outcome as well as psychopathological dimensions of schizophrenia. STUDY DESIGN: First-admitted patients (N = 121) diagnosed with non-affective psychosis, schizotypal disorder, or other mental illness were examined at initial hospitalization and 5 years later with a comprehensive assessment of psychopathology. Informed by the literature, we constructed scales targeting pseudoneurotic symptoms and other, more general, nonpsychotic symptoms. STUDY RESULTS: Pseudoneurotic symptoms aggregated in schizophrenia-spectrum groups compared to other mental illnesses and occurred at similar levels at baseline and follow-up. They longitudinally predicted poorer social and occupational functioning in schizophrenia-spectrum patients over a 5-year-period but not transition to schizophrenia-spectrum disorders from other mental illnesses. Finally, the level of pseudoneurotic symptoms correlated with disorder of basic self at both assessments and with positive and negative symptoms at follow-up. The scale targeting general nonpsychotic symptoms did not show this pattern of associations. CONCLUSIONS: The study supports that a group of nonpsychotic symptoms, ie, pseudoneurotic symptoms, are associated with schizophrenia-spectrum disorders and linked with temporally stable psychopathology, particularly disorder of the basic self. Their prospective association with social and occupational functioning needs replication.

The self, neuroscience and psychosis study: Testing a neurophenomenological model of the onset of psychosis.

AIM: Basic self disturbance is a putative core vulnerability marker of schizophrenia spectrum disorders. The primary aims of the Self, Neuroscience and Psychosis (SNAP) study are to: (1) empirically test a previously described neurophenomenological self-disturbance model of psychosis by examining the relationship between specific clinical, neurocognitive, and neurophysiological variables in UHR patients, and (2) develop a prediction model using these neurophenomenological disturbances for persistence or deterioration of UHR symptoms at 12-month follow-up. METHODS: SNAP is a longitudinal observational study. Participants include 400 UHR individuals, 100 clinical controls with no attenuated psychotic symptoms, and 50 healthy controls. All participants complete baseline clinical and neurocognitive assessments and electroencephalography. The UHR sample are followed up for a total of 24 months, with clinical assessment completed every 6 months. RESULTS: This paper presents the protocol of the SNAP study, including background rationale, aims and hypotheses, design, and assessment procedures. CONCLUSIONS: The SNAP study will test whether neurophenomenological disturbances associated with basic self-disturbance predict persistence or intensification of UHR symptomatology over a 2-year follow up period, and how specific these disturbances are to a clinical population with attenuated psychotic symptoms. This may ultimately inform clinical care and pathoaetiological models of psychosis.

Anomalies of imagination and development of psychosis: A phenomenological account.

In 20th century psychiatry, various disturbances of imagination were discussed in the context of schizophrenia. Today, these notions have almost completely vanished from mainstream psychopathology. However, recent work has suggested that specific phenomena within this area have a relevance for differential diagnosis and early detection of psychosis. This paper first provides an overview of 20th century psychopathological literature, as well as more recent neurocognitive studies, addressing disturbances of imagination and their role for symptom formation in schizophrenia. It then discusses recent empirical investigations of subjective anomalies of imagination in schizophrenia-spectrum disorders and suggests a clinical-phenomenological account of their role in the development of psychotic symptoms. Empirically and conceptually, these subjective anomalies are linked with disturbances of basic self. Patients' descriptions of the development of their anomalous experiences and symptoms indicate that increased spatial (object-like) articulation and instability of the first-personal manifestation of imaginative experience can be involved in the emergence of delusions and hallucinatory phenomena. Finally, a potential link between subjective anomalies of imagination and the neurocognitive construct of source monitoring deficits is discussed.

Treatment of schizotypal disorder: a protocol for a systematic review of the evidence and recommendations for clinical practice.

INTRODUCTION: Schizotypal disorder is associated with a high level of disability at an individual level and high societal costs. However, clinical recommendations for the treatment of schizotypal disorder are scarce and based on limited evidence. This review aims to synthesise the current evidence on treatment for schizotypal disorder making recommendations for clinical practice. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic literature search will be performed in PsychArticles, Embase, Medline and Cochrane Central Register of Controlled Trials. Additionally, we will search for relevant articles manually. Inclusion criteria are published studies including individuals diagnosed with schizotypal personality disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, or schizotypal disorder according to International Classification of Diseases (ICD) criteria. We will include interventional studies comprising any pharmacological and non-pharmacological treatment trials for patients with schizotypal disorder, and all relevant outcome measures will be reported. Risk of bias will be assessed by Cochrane risk-of-bias tools. Data will be synthesised using narrative or thematic analysis and, if suitable, through meta-analysis. ETHICS AND DISSEMINATION: No original data will be collected as part of this study and ethics approval is, therefore, not applicable. The results will be disseminated through peer-reviewed publication and presented at international scientific meetings. We will aim at submitting the final paper for publication within 4 months of completion of analyses. Furthermore, this systematic review will inform clinicians and researchers on the current state of evidence on treatment for schizotypal disorder. Findings may guide proposals for further research and potentially guide recommendations for clinical practice using the Grading of Recommendations Assessment, Development and Evaluation. PROSPERO REGISTRATION NUMBER: CRD42022375001.

Quartz-Enhanced Photoacoustic Spectroscopy Assisted by Partial Least-Squares Regression for Multi-Gas Measurements.

We report on the use of quartz-enhanced photoacoustic spectroscopy (QEPAS) for multi-gas detection. Photoacoustic (PA) spectra of mixtures of water (H2O), ammonia (NH3), and methane (CH4) were measured in the mid-infrared (MIR) wavelength range using a mid-infrared (MIR) optical parametric oscillator (OPO) light source. Highly overlapping absorption spectra are a common challenge for gas spectroscopy. To mitigate this, we used a partial least-squares regression (PLS) method to estimate the mixing ratio and concentrations of the individual gasses. The concentration range explored in the analysis varies from a few parts per million (ppm) to thousands of ppm. Spectra obtained from HITRAN and experimental single-molecule reference spectra of each of the molecular species were acquired and used as training data sets. These spectra were used to generate simulated spectra of the gas mixtures (linear combinations of the reference spectra). Here, in this proof-of-concept experiment, we demonstrate that after an absolute calibration of the QEPAS cell, the PLS analyses could be used to determine concentrations of single molecular species with a relative accuracy within a few % for mixtures of H2O, NH3, and CH4 and with an absolute sensitivity of approximately 300 (±50) ppm/V, 50 (±5) ppm/V, and 5 (±2) ppm/V for water, ammonia, and methane, respectively. This demonstrates that QEPAS assisted by PLS is a powerful approach to estimate concentrations of individual gas components with considerable spectral overlap, which is a typical scenario for real-life adoptions and applications.

Psychiatric comorbidity: a concept in need of a theory.

Despite being a relatively new concept, psychiatric comorbidity, i.e. the co-occurrence of two or more mental disorders, has become widespread in clinical practice and psychiatric research. In this article, we trace the origin of the concept of psychiatric comorbidity, discuss the conceptual literature and point to basic problems concerning inadequate definition of the concept, differential diagnostic issues, and reification of mental disorders. We illustrate how these problems may have consequences for diagnostic assessment in current clinical practice and psychiatric research. To address some of the problems related to psychiatric comorbidity, we discuss potential principles for assessing psychiatric comorbidity. Inspired by Feinstein's original concept of comorbidity in general medicine and his differential diagnostic principles, we emphasize the importance of independence of mental disorders when assessing psychiatric comorbidity. We suggest that knowledge of trait v. state conditions and of the multitudinous clinical manifestations beyond what is captured in the diagnostic manuals may be helpful for assessing the independence of mental disorders and thus psychiatric comorbidity. We further argue that a more hierarchical diagnostic system and explicit exclusionary rules could improve clinical practice and research by reducing informational complexity and combating unwarranted psychiatric comorbidity.

Obsessive-compulsive symptoms in the schizophrenia-spectrum: current developments in psychopathology research.

PURPOSE OF REVIEW: Schizophrenia-spectrum disorders (SSD) frequently involve symptoms that usually are ascribed to nonpsychotic disorder spectra, such as obsessive-compulsive symptoms (OCS). These symptoms can cause differential diagnostic challenges, particularly in early illness stages, and must be considered in treatment planning. In this review, we provide an overview of recent literature within the field of OCS in SSD, with a focus on psychopathology research. RECENT FINDINGS: OCS are seen in approximately a quarter of patients with SSD or at-risk mental state of psychosis. They are associated with more severe clinical features and specific temporal patterns of OCS may be linked with different clinical trajectories. However, the current definitions of OCS have been criticized for their overinclusive nature, which is a limiting step for differential diagnosis and more precise prognostic stratification. Specific phenomenological features, including a link with experiential anomalies (disorders of basic self), have been suggested to provide clinically relevant distinctions. SUMMARY: The presence of OCS in SSD is associated with more severe clinical features and invites a higher clinical attention and perspectival monitoring. Some findings suggest that more fine-grained psychopathological distinctions might be a viable clinical and research strategy to advance the field in the direction of precision psychiatry.

Are Self-disorders in Schizophrenia Expressive of a Unifying Disturbance of Subjectivity: A Factor Analytic Approach.

BACKGROUND AND HYPOTHESIS: The idea that a disorder of the basic self is a central feature in schizophrenia has recently been corroborated in a meta-analysis and a systematic review. Manifestations of the self-disorder can be systematically explored with the Examination of Anomalous Self-Experience (EASE). In this study, we examined the factorial structure of EASE, and diagnostic efficacy of EASE. We hypothesized that EASE will have a monofactorial structure as an instability of the basic self will result in multiple deformations of self-experience which would be meaningfully interrelated as aspects of a unifying Gestalt. DESIGN: EASE data for 226 patients suffering from various mental disorders were analyzed under a confirmatory factor analysis framework (CFA). Area under the receiver operating characteristic curve (AUC) was calculated for the total EASE sums, and sensitivity and specificity values for prediction of schizophrenia spectrum disorders based on different cut-offs were obtained. RESULTS: Fit indices for the CFA model: RMSEA = 0.036, SRMR = 0.100, CFI = 0.983, TLI = 0.981. The AUC value was 0.946 (95% confidence interval: 0.919-0.974). Sensitivity as well as specificity for schizophrenia spectrum disorders were high. CONCLUSION: Our results lend support for EASE exhibiting a monofactorial structure and the notion of self-disorders as a central phenotypic feature of schizophrenia spectrum disorders.

Pseudoneurotic symptoms in the schizophrenia spectrum: An empirical study.

BACKGROUND: Nonpsychotic symptoms (depression, anxiety, obsessions etc.) are frequent in schizophrenia-spectrum disorders. Twentieth century foundational psychopathological literature claimed that certain nonpsychotic symptoms (here termed pseudoneurotic symptoms) are relatively closely linked with the schizophrenia-spectrum, despite descriptive overlap with symptoms of other diagnoses. In this study, we investigated the association of pseudoneurotic and other nonpsychotic symptoms with the schizophrenia-spectrum as well as a hypothesis about an association of pseudoneurotic symptoms with disorder of basic self. METHODS: The sample (N = 226) comprised patients with non-affective psychosis (N = 119), schizotypal personality disorder (N = 51) and other mental illness (N = 56), who were examined with a comprehensive assessment of lifetime psychopathology. Informed by the literature, we constructed scales targeting pseudoneurotic symptoms and other, more general, nonpsychotic symptoms. RESULTS: Pseudoneurotic symptoms aggregated significantly in schizophrenia-spectrum disorders with an Area under the receiver operating characteristic curve of 0.84 (SE 0.03) for classifying patients with schizophrenia-spectrum disorders versus other mental illness. Patients with non-affective psychosis scored slightly, but significantly, higher on the scale targeting general nonpsychotic symptomatology than the other groups. In multiple regression analysis, pseudoneurotic symptoms were predicted by general nonpsychotic symptoms, disorders of basic self, and negative symptoms but not positive symptoms. CONCLUSION: The study supports that certain neurotic-like symptoms with specific descriptive features (pseudoneurotic symptoms) are associated with schizophrenia-spectrum disorders. It suggests that pseudoneurotic symptoms are linked with temporally stable schizophrenia psychopathology (disorder of basic self and negative symptoms).

What is obsession? Differentiating obsessive-compulsive disorder and the schizophrenia spectrum.

Obsessive-compulsive symptoms are frequent in schizophrenia-spectrum disorders and often cause differential diagnostic challenges, especially in first-contact patients. Drawing upon phenomenology of cognition, we critically review classic and contemporary psychopathological notions of obsessive-compulsive phenomena and discuss their relevance for differential diagnosis between obsessive-compulsive disorder (OCD) and schizophrenia-spectrum disorders. The classic psychopathological literature defines true obsession as intrusions with intact resistance and insight and regards these features as essential to the diagnosis of OCD. In schizophrenia, the classic literature describes pseudo-obsessive-compulsive phenomena characterized by lack of resistance and an affinity with other symptoms such as thought disorder and catatonia. By contrast, the notions of obsession and compulsion are broader and conceptually vague in current diagnostic systems and research instruments. Here, these phenomena overlap with delusions as well as various subjective and behavioral anomalies, which we discuss in detail. Furthermore, we examine a link between obsessive-compulsive phenomena and disturbances of basic structures of experience in schizophrenia-spectrum disorders addressed in contemporary psychopathological research. We suggest that these experiential alterations have relevance for differential diagnosis and early detection in this complex symptom domain.

Disordered Selfhood in Schizophrenia and the Examination of Anomalous Self-Experience: Accumulated Evidence and Experience.

Disordered selfhood in schizophrenia was rediscovered at the turn of the millennium. In 2005, Psychopathology published the psychometric instrument, the Examination of Anomalous Self-Experience (EASE). In this article, we summarize the historical background of the creation of the EASE, explicate the notion of the disorder of basic or minimal self with the help of phenomenological philosophy, and provide a brief description of clinical manifestations targeted by the EASE. We also present our personal experience using and teaching the EASE and summarize the empirical evidence obtained so far. We conclude that the basic self-disorder represents a crucial phenotype of schizophrenia spectrum disorders and that this phenotype offers a potential avenue to empirical pathogenetic research and psychotherapeutic treatment.

The Copenhagen founder variant GP1BA c.58T>G is the most frequent cause of inherited thrombocytopenia in Denmark.

BACKGROUND: The classic Bernard-Soulier syndrome (BSS) is a rare inherited thrombocytopenia (IT) associated with severe thrombocytopenia, giant platelets, and bleeding tendency caused by homozygous or compound heterozygous variants in GP1BA, GP1BB, or GP9. Monoallelic BSS (mBSS) associated with mild asymptomatic macrothrombocytopenia caused by heterozygous variants in GP1BA or GP1BB may be a frequent cause of mild IT. OBJECTIVE: We aimed to examine the frequency of mBSS in a consecutive cohort of patients with IT and to characterize the geno- and phenotype of mBSS probands and their family members. Additionally, we set out to examine if thrombopoietin (TPO) levels differ in mBSS patients. PATIENTS/METHODS: We screened 106 patients suspected of IT using whole exome- or whole genome sequencing and performed co-segregation analyses of mBSS families. All probands and family members were phenotypically characterized. Founder mutation analysis was carried out by certifying that the probands were unrelated and the region around the variant was shared by all patients. TPO was measured by solid phase sandwich ELISA. RESULTS: We diagnosed 14 patients (13%) with mBSS associated with heterozygous variants in GP1BA and GP1BB. Six unrelated probands carried a heterozygous variant in GP1BA (c.58T>G, p.Cys20Gly) and shared a 2.0 Mb region on chromosome 17, confirming that it is a founder variant. No discrepancy of TPO levels between mBSS patients and wild-type family members (P > .05) were identified. CONCLUSION: We conclude that the most frequent form of IT in Denmark is mBSS caused by the Copenhagen founder variant.

Substitutional landscape of a split fluorescent protein fragment using high-density peptide microarrays.

Split fluorescent proteins have wide applicability as biosensors for protein-protein interactions, genetically encoded tags for protein detection and localization, as well as fusion partners in super-resolution microscopy. We have here established and validated a novel platform for functional analysis of leave-one-out split fluorescent proteins (LOO-FPs) in high throughput and with rapid turnover. We have screened more than 12,000 variants of the beta-strand split fragment using high-density peptide microarrays for binding and functional complementation in Green Fluorescent Protein. We studied the effect of peptide length and the effect of different linkers to the solid support. We further mapped the effect of all possible amino acid substitutions on each position as well as in the context of some single and double amino acid substitutions. As all peptides were tested in 12 duplicates, the analysis rests on a firm statistical basis allowing for confirmation of the robustness and precision of the method. Based on experiments in solution, we conclude that under the given conditions, the signal intensity on the peptide microarray faithfully reflects the binding affinity between the split fragments. With this, we are able to identify a peptide with 9-fold higher affinity than the starting peptide.

Chronic migraine: Genetics or environment?

BACKGROUND: The transition from episodic migraine to chronic migraine, migraine chronification, is usually a gradual process, which involves multiple risk factors. To date, studies of the genetic risk factors for chronic migraine have focused primarily on candidate-gene approaches using healthy individuals as controls. AIMS AND METHODS: In this study, we used a large cohort of migraine families and unrelated migraine patients (n > 2200) with supporting genotype and whole-genome sequencing data. We evaluated whether there are any genetic variants, common or rare, with a specific association to chronic migraine compared with episodic migraine. RESULTS: We found no aggregation of chronic migraine in families with a clustering of migraine. No specific rare variants gave rise to migraine chronification, and migraine chronification was not associated with a higher polygenic risk score. Migraine chronification was not associated with allelic associations with an odds ratio above 2.65. Assessment of effect sizes with genome-wide significance below an odds ratio of 2.65 requires a genome-wide association study of at least 7500 chronic migraine patients. CONCLUSION: Our results suggest that migraine chronification is caused by environmental factors rather than genetic factors.

Anomalies of Imagination, Self-Disorders, and Schizophrenia Spectrum Psychopathology: A Network Analysis.

BACKGROUND: Anomalies of imagination encompass disturbances of the basic experiential structure of fantasies and imagery that can be explored in a semi-structured way with the Examination of Anomalous Fantasy and Imagination (EAFI). We aimed (1) to examine the distribution of anomalies of imagination among different diagnostic groups and a group of healthy controls, and (2) to examine their relation with disorders of basic self, perceptual disturbances and canonical state psychopathology of the schizophrenia-spectrum (positive, negative and general symptoms). METHODS: The 81 participants included patients with schizophrenia or other non-affective psychosis (N = 32), schizotypal personality disorder (N = 15) or other mental illness (N = 16) and healthy controls (N = 18). The assessment encompassed EAFI, Examination of Anomalous Self-Experience (EASE), parts of Bonn Scale for the Assessment of Basic Symptoms (BSABS) and Positive and Negative Syndrome Scale (PANSS). For network analysis, the associations of EAFI with the other psychopathological variables were tested by Pearson's correlation coefficient and graphically represented using multidimensional clustering. Comparisons between correlations in the network were tested with Steiger's test. RESULTS: Anomalies of imagination aggregated significantly in schizophrenia-spectrum disorders compared to other mental illness and healthy controls with no difference between schizophrenia and schizotypal disorder. In the network analysis, anomalies of imagination were closely inter-connected with self-disorders. Although, the anomalies of imagination correlated moderately with perceptual disturbance and positive, negative and general state symptomatology, these dimensions aggregated separately and relatively distant in the network. CONCLUSIONS: The results support that anomalies of imagination are highly characteristic of schizophrenia-spectrum disorders and closely related to self-disorders.

Functional gene networks reveal distinct mechanisms segregating in migraine families.

Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors - a population-based study.

INTRODUCTION: Headache is an extremely prevalent disorder with a lifetime prevalence of 90-99%. However, a small fraction of people never experiences a headache. Research on people without headache could uncover protective factors in headache, but to our knowledge no study on headache-free individuals has been published. We aim to estimate the prevalence of headache-free individuals among Danish blood donors, and to describe the socio-demographics and health factors of headache-free participants. MATERIALS AND METHODS: In all, 38,557 healthy volunteers were recruited as part of the Danish Blood Donor Study. Headache-free participants were identified based on the question "Have you ever experienced a headache of any kind?". Utilising the Danish registries and self-reported questionnaires, we analysed socio-demographic and lifestyle factors using logistic regression adjusted for age and sex. RESULTS: The prevalence of headache-free individuals was 4.1% (n = 1362) with a female-male ratio of 1:2.2. To be headache free was significantly associated with an employment status as a student, a low level of income and a regular alcohol consumption. DISCUSSION: The prevalence of headache-free individuals was comparable to population-wide studies of headache. To be headache free was not associated with a high socio-economic status. Further studies on people without headache will hopefully reveal protective factors in headache, and this novel approach might be useful in other very prevalent disorders.

Familial analysis reveals rare risk variants for migraine in regulatory regions.

The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.