Verneri Anttila

Broad Institute of MIT and Harvard · Program in Medical and Population Genetics

Background: The precise relation between migraine and cardiovascular diseases remains unknown, but cardiac autonomic regulation as reflected by electrocardiography is poorly studied in migraineurs. Aims of the study: To search whether electrocardiographic findings may elucidate the mechanisms linking migraine with cardiovascular diseases. Metho...

Background The influence of cardiovascular risk factors on the probability of cardiovascular diseases in migraineurs is still being discussed. Aims of the Study To further elucidate the mechanisms of these relationships, we assessed the associations between migraine and cardiovascular risk factors, including those that have been recently shown to...

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3...

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity...

In the Data Availability Statement, the URL does not fully match the data described. The URL should be: https://doi.org/10.17863/CAM.36024. The correct Data Availability Statement is: Summary statistic GWAS meta-analysis results for the combined dataset excluding 23andMe are available at https://doi.org/10.17863/CAM.36024. The most significant 10,0...

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hypera...

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hypera...

Abstract Recent technical advances in genetics made large-scale genome-wide association studies (GWAS) in migraine feasible and have identified over 40 common DNA sequence variants that affect risk for migraine types. Most of the variants, which are all single nucleotide polymorphisms (SNPs), show robust association with migraine as evidenced by th...

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a pheno...

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from...

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from...

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small...

We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest...

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a pheno...

Advances in recent genome wide association studies (GWAS) suggest that pleiotropic effects on human complex traits are widespread. A number of classic and recent meta-analysis methods have been used to identify genetic loci with pleiotropic effects, but the overall performance of these methods is not well understood. In this work, we use extensive...

Power of ten meta analysis methods for ten traits when 25% effects are in the opposite direction (alpha = 0.05, OR = 1.1, K = 10). (PDF)

Power of ten meta analysis methods for ten traits when 50% effects are in the opposite direction (alpha = 0.001, OR = 1.2, K = 10). (PDF)

Power of ten meta analysis methods for five traits when all effects are in the same direction (alpha = 0.05, OR = 1.1, K = 5). (PDF)

Power of ten meta analysis methods for five traits when 25% effects are in the opposite direction (alpha = 0.05, OR = 1.1, K = 5). (PDF)

Power of ten meta analysis methods for five traits when all effects are in the same direction (alpha = 0.001, OR = 1.2, K = 5). (PDF)

Three distributions of effect sizes under odds ratios of 1.1 and 1.2. (PDF)

Power of ten meta analysis methods for ten traits when all effects are in the same direction (alpha = 0.05, OR = 1.1, K = 10). (PDF)

Power of ten meta analysis methods for ten traits when 50% effects are in the opposite direction (alpha = 0.05, OR = 1.1, K = 10). (PDF)

Power of ten meta analysis methods for five traits when 50% effects are in the opposite direction (alpha = 0.001, OR = 1.2, K = 5). (PDF)

False positive rates of ASSET, CPASSOC, and WICS with overlapping samples. (XLSX)

Power of ten meta analysis methods for five traits when 50% effects are in the opposite direction (alpha = 0.05, OR = 1.1, K = 5). (PDF)

Power of ten meta analysis methods for five traits when 25% effects are in the opposite direction (alpha = 0.001, OR = 1.2, K = 5). (PDF)

Power of ten meta analysis methods for ten traits when all effects are in the same direction (alpha = 0.001, OR = 1.2, K = 10). (PDF)

Power of ten meta analysis methods for ten traits when 25% effects are in the opposite direction (alpha = 0.001, OR = 1.2, K = 10). (PDF)

QQ plots of meta analysis results for five neuropsychiatric disorders. (PDF)

Manhattan plots of meta analysis results for five neuropsychiatric disorders. (PDF)

Type I error rates of ten meta analysis methods. (XLSX)

Sensitivity and specificity of meta analysis methods, ASSET, BE, and CPASSOC. (XLSX)

Details of genome-wide significant loci identified by ten meta-analysis methods. (XLSX)

Summary of evaluated methods. (PDF)

Genetics of migraine has recently undergone a major shift, moving in the space of a few years from having only a few known genes for rare Mendelian forms to 47 known common variant loci affecting the susceptibility of the common forms of migraine. This has largely been achieved by rapidly increasing sample sizes for genomewide association studies (...

It has long been observed that complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. Two competing hypotheses exist, emphasizing either rare or common genetic variation. More specifically, familial aggregation could be predominantly explained by rare, penetrant v...

Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the ge...

Genetic cross-phenotype enrichment of migraine conditional on CAD after excluding PHACTR1. Genome-wide analysis after excluding all SNPs in PHACTR1 as well as any SNPs in linkage disequilibrium (r2 > 0.1) with these. (a-b) Conditional Q-Q plot of nominal versus empirical -log10 P-values (corrected for inflation) in CAD as a function of significance...

Previously reported genome-wide significant associations in LD (r2 > 0.1) with the identified cross-phenotype loci. LD calculations are based on the European CEU population in the Phase 3 of the 1000 Genomes Project, as implemented in LDlink [30]. Reported associations are taken from the NHGRI GWAS catalog [31]. * PubMed ID for publication(s). (DOC...

DEPICT analysis of gene expression enrichment in specific tissues. The analysis was based on expression data obtained from 37,427 human microarray samples for 209 tissue or cell types, as implemented in DEPICT [28]. Genes in loci with conjuctional FDR < 0.4 for cross-phenotype association between migraine and CAD were assessed for high expression i...

DEPICT analysis of gene set enrichment. DEPICT reconstituted gene sets showing strongest evidence for enrichment for genes in loci with conjuctional FDR < 0.4 for cross-phenotype association between migraine against CARDIoGRAM (a) and for migraine against C4D (b). No reconstituted gene sets was significantly enriched (false discovery rate <0.05) af...

SNPs showing suggestive evidence (conjunctional FDR < 0.1) for shared association to migraine and coronary artery disease (CAD). SNP, Single nucleotide polymorphism; Chr, Chromosome; CAD, Coronary artery disease; FDR, False discovery rate. SE, standard error. na, SNP not available for analysis. *Positions refer to build NCBI36/hg18. †Conjunctional...

Genetics can provide a systematic approach to discovering the tissues and cell types relevant for a complex disease or trait. Identifying these tissues and cell types is critical for following up on non-coding allelic function, developing ex-vivo models, and identifying therapeutic targets. Here, we analyze gene expression data from several sources...

Disorders of the brain exhibit considerable epidemiological comorbidity and frequently share symptoms, provoking debate about the extent of their etiologic overlap. We quantified the genetic sharing of 25 brain disorders based on summary statistics from genome-wide association studies of 215,683 patients and 657,164 controls, and their relationship...

Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. Objective To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subt...

Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample s...

Objective: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anor...

Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement “hotspot” loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted. Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously pub...

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to s...

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We in...

Migraine affects ∼14% of the world's population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sample Mendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated...

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency...

Quantile-quantile plot of observed against expected p-values for the Health 2000 GWAS of sciatica. Results are adjusted for the first seven principal components of genetic data, and for sex and age. (TIF)

Minor allele frequencies for the five most promising variants in the Finnish and other European populations. (DOCX)

The most promising variants in the GWAS meta-analysis of sciatica (p<1x10-6) as tested for replication in a Finnish population-based cohort (FINRISK). (DOCX)

Raw result data of the meta-analysis (with variants with p < 0.001). (TXT)

Quantile-quantile plot of observed against expected p-values for the genome-wide meta-analysis of sciatica. (TIF)

Manhattan plot for the Young Finns Study GWAS of sciatica. Results are adjusted for the first seven principal components of genetic data and for sex and age. Variants in red have p-value below genome-wide significance level (p < 5x10-8). (TIFF)

Study analysis methods. Methods used in genotyping, imputation, genome-wide association study and meta-analysis. (DOCX)

Variants associated with sciatica in the meta-analysis (p < 1x10-6) with effect allele frequencies, imputation quality and p-values in two discovery GWAS. (DOCX)

LD estimates from the YFS (upper diagonal in green) and H2000 (lower diagonal in yellow) for SNPs with p<5x10-8 within the locus 15q21.2. (DOCX)

Supplementary References. (DOCX)

Quantile-quantile plot of observed against expected p-values for the Young Finns Study GWAS of sciatica. Results are adjusted for the first seven principal components of genetic data and for sex and age. (TIF)

Manhattan plot for the Health 2000 GWAS of sciatica. Results are adjusted for the first seven principal components of genetic data, and for sex and age. (TIF)