Statistical analysis of the associations of hereditary factors with the risk of Type 1 diabetes and Diabetic Nephropathy based on the familial data collected through ascertaiment from population-based registers

In genetic epidemiology, population-based disease registries are commonly used to collect genotype or other risk factor information concerning affected subjects and their relatives. This work presents two new approaches for the statistical inference of ascertained data: a conditional and full likelihood approaches for the disease with variable age at onset phenotype using familial data obtained from population-based registry of incident cases. The aim is to obtain statistically reliable estimates of the general population parameters. The statistical analysis of familial data with variable age at onset becomes more complicated when some of the study subjects are non-susceptible, that is to say these subjects never get the disease. A statistical model for a variable age at onset with long-term survivors is proposed for studies of familial aggregation, using latent variable approach, as well as for prospective studies of genetic association studies with candidate genes. In addition, we explore the possibility of a genetic explanation of the observed increase in the incidence of Type 1 diabetes (T1D) in Finland in recent decades and the hypothesis of non-Mendelian transmission of T1D associated genes. Both classical and Bayesian statistical inference were used in the modelling and estimation. Despite the fact that this work contains five studies with different statistical models, they all concern data obtained from nationwide registries of T1D and genetics of T1D. In the analyses of T1D data, non-Mendelian transmission of T1D susceptibility alleles was not observed. In addition, non-Mendelian transmission of T1D susceptibility genes did not make a plausible explanation for the increase in T1D incidence in Finland. Instead, the Human Leucocyte Antigen associations with T1D were confirmed in the population-based analysis, which combines T1D registry information, reference sample of healthy subjects and birth cohort information of the Finnish population. Finally, a substantial familial variation in the susceptibility of T1D nephropathy was observed. The presented studies show the benefits of sophisticated statistical modelling to explore risk factors for complex diseases.

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, approximately 0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

Mutation analysis of TGF-β signaling pathway genes among Finnish patients with primary pulmonary hypertension and hereditary hemorrhagic telangiectasia

Primary pulmonary hypertension (PPH), or according to the recent classification idiopathic pulmonary hypertension (IPAH), is a rare, progressive disease of pulmonary vasculature leading to pulmonary hypertension and right heart failure. Most of the patients are sporadic but in about 6% of cases the disease is familial (FPPH). In 2000 two different groups identified the gene predisposing to PPH. This gene, Bone morphogenetic protein receptor type 2 (BMPR2), encodes a subunit of transforming growth factor β (TGF-β) receptor complex. There is a genetic connection between PPH and hereditary hemorrhagic telangiectasia (HHT), a bleeding disorder characterized by local telangiectasias and sometimes with pulmonary hypertension. In HHT, mutations in ALK1 (activin like kinase type 1) and Endoglin, another members of the TGF-β signaling pathway are found. In this study we identified all of the Finnish PPH patients for the years 1986-1999 using the hospital discharge registries of Finnish university hospitals. During this period we found a total of 59 confirmed PPH patients: 55 sporadic and 4 familial representing 3 different families. In 1999 the prevalence of PPH was 5.8 per million and the annual incidence varied between 0.2-1.3 per million. Among 28 PPH patients studied, heterozygous BMPR2 mutations were found in 12% (3/26) of sporadic patients and in 33% of the PPH families (1/3). All the mutations found were different. Large deletions of BMPR2 were excluded by single-stranded chain polymomorphism analysis. As a candidate gene approach we also studied ALK1, Endoglin, Bone Morphogenetic Receptor Type IA (BMPR1A or ALK3), Mothers Against Decapentaplegic Homolog 4 (SMAD4) and Serotonine Transporter Gene (SLC6A4) using single-strand conformational polymorphism (SSCP) analysis and direct sequencing. Among patients and family members studied, we found two mutations in ALK1 in two unrelated samples. We also identified all the HHT patients treated at the Department of Otorhinolaryngology at Helsinki University Central Hospital between the years of 1990-2005 and 8 of the patients were studied for Endoglin and ALK1 mutations using direct sequencing. A total of seven mutations were found and all the mutations were different. The absence of a founder mutation in the Finnish population in both PPH and HHT was somewhat surprising. This suggests that the mutations of BMPR2, ALK1 and Endoglin are quite young and the older mutations have been lost due to repetitive genetic bottlenecks and/or negative selection. Also, other genes than BMPR2 may be involved in the pathogenesis of PPH. No founder mutations were found in PPH or HHT and thus no simple genetic test is available for diagnostics.

Meta-analysis of genome-wide association for migraine in six population-based European cohorts

Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10,980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value<10(-5). The best result was obtained for SNP rs9908234, which had a P-value of 8.00 x 10(-8). This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate.

Molecular Genetics of Schizophrenia and Related Intermediate Phenotypes in a Founder Population

Schizophrenia, affecting about 1% of population worldwide, is a severe mental disorder characterized by positive and negative symptoms, such as psychosis and anhedonia, as well as cognitive deficits. At present, schizophrenia is considered a complex disorder of neurodevelopmental origin with both genetic and environmental factors contributing to its onset. Although a number of candidate genes for schizophrenia have been highlighted, only very few schizophrenia patients are likely to share identical genetic liability. This study is based on the nation-wide schizophrenia family sample of the National Institute for Health and Welfare, and represents one of the largest and most well-characterized familial series in the world. In the first part of this study, we investigated the roles of the DTNBP1, NRG1, and AKT1 genes in the background of schizophrenia in Finland. Although these genes are associated with schizophrenia liability in several populations, any significant association with clinical diagnostic information of schizophrenia remained absent in our sample of 441 schizophrenia families. In the second part of this study, we first replicated schizophrenia linkage on the long arm of chromosome 7 in 352 schizophrenia families. In the following association analysis, we utilized additional clinical disorder features and intermediate phenotypes – endophenotypes - in addition to diagnostic information from altogether 290 neuropsychologically assessed schizophrenia families. An intragenic short tandem repeat allele of the regional RELN gene, supposed to play a role in the background of several neurodevelopmental disorders, showed significant association with poorer cognitive functioning and more severe schizophrenia symptoms. Additionally, this risk allele was significantly more prevalent among the individuals affected with schizophrenia spectrum disorders. We have previously identified linkage of schizophrenia and its cognitive endophenotypes on the long arms of chromosomes 2, 4, and 5. In the last part of this study, we selected altogether 104 functionally relevant candidate genes from the linked regions. We detected several promising associations, of which especially interesting are the ERBB4 gene, showing association with the severity of schizophrenia symptoms and impairments in traits related to verbal abilities, and the GRIA1 gene, showing association with the severity of schizophrenia symptoms. Our results extend the previous evidence that the genetic risk for schizophrenia is at least partially mediated via the effects of the candidate genes and their combinations on relevant brain systems, resulting in alterations in different disorder domains, such as the cognitive deficits.

GM solutions to root diseases of cereals - A situation analysis and business case

Root disease causes about $503 million in losses annually to Australia's wheat and barley industries. Because of these large losses and in many cases the difficulty in reducing these losses through breeding or management, root diseases are candidates for solutions through genetic modification (GM). Through an extensive review of the scientific literature and patents, a range of approaches to GM solutions to root diseases are critically discussed. Given the high cost of regulatory approval for GM crops and a complex intellectual property (IP) landscape, it is likely that research in this area will be done in collaboration with international partners.

Insights into the molecular genetics of celiac disease : Applying family- and population-based strategies

Celiac disease, or gluten intolerance, is triggered by dietary glutens in genetically susceptible individuals and it affects approximately 1% of the Caucasian population. The best known genetic risk factors for celiac disease are HLA DQ2 and DQ8 heterodimers, which are necessary for the development of the disease. However, they alone are not sufficient for disease induction, other risk factors are required. This thesis investigated genetic factors for celiac disease, concentrating on susceptibility loci on chromosomes 5q31-q33, 19p13 and 2q12 previously reported in genome-wide linkage and association studies. In addition, a novel genotyping method for the detection of HLA DQ2 and DQ8 coding haplotypes was validated. This study was conducted using Finnish and Hungarian family materials, and Finnish, Hungarian and Italian case-control materials. Genetic linkage and association were analysed in these materials using candidate gene and fine-mapping approaches. The results confirmed linkage to celiac disease on the chromosomal regions 5q31-q33 and 19p13. Fine-mapping on chromosome 5q31-q33 revealed several modest associations in the region, and highlighted the need for further investigations to locate the causal risk variants. The MYO9B gene on chromosome 19p13 showed evidence for linkage and association particularly with dermatitis herpetiformis, the skin manifestation of celiac disease. This implies a potential difference in the genetic background of the intestinal and skin forms of the disease, although studies on larger samplesets are required. The IL18RAP locus on chromosome 2q12, shown to be associated with celiac disease in a previous genome-wide association study and a subsequent follow-up, showed association in the Hungarian population in this study. The expression of IL18RAP was further investigated in small intestinal tissue and in peripheral blood mononuclear cells. The results showed that IL18RAP is expressed in the relevant tissues. Two putative isoforms of IL18RAP were detected by Western blot analysis, and the results suggested that the ratios and total levels of these isoforms may contribute to the aetiology of celiac disease. A novel genotyping method for celiac disease-associated HLA haplotypes was also validated in this thesis. The method utilises single-nucleotide polymorphisms tagging these HLA haplotypes with high sensitivity and specificity. Our results suggest that this method is transferable between populations, and it is suitable for large-scale analysis. In conclusion, this doctorate study provides an insight into the roles of the 5q31-q33, MYO9B, IL18RAP and HLA loci in the susceptibility to celiac disease in the Finnish, Hungarian and Italian populations, highlighting the need for further studies at these genetic loci and examination of the function of the candidate genes.

Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

Susceptibility locus on chromosome 1q23-25 for a schizophrenia subtype resembling deficit schizophrenia identified by latent class analysis

Context: Identifying susceptibility genes for schizophrenia may be complicated by phenotypic heterogeneity, with some evidence suggesting that phenotypic heterogeneity reflects genetic heterogeneity. Objective: To evaluate the heritability and conduct genetic linkage analyses of empirically derived, clinically homogeneous schizophrenia subtypes. Design: Latent class and linkage analysis. Setting: Taiwanese field research centers. Participants: The latent class analysis included 1236 Han Chinese individuals with DSM-IV schizophrenia. These individuals were members of a large affected-sibling-pair sample of schizophrenia (606 ascertained families), original linkage analyses of which detected a maximum logarithm of odds (LOD) of 1.8 (z = 2.88) on chromosome 10q22.3. Main Outcome Measures: Multipoint exponential LOD scores by latent class assignment and parametric heterogeneity LOD scores. Results: Latent class analyses identified 4 classes, with 2 demonstrating familial aggregation. The first (LC2) described a group with severe negative symptoms, disorganization, and pronounced functional impairment, resembling “deficit schizophrenia.” The second (LC3) described a group with minimal functional impairment, mild or absent negative symptoms, and low disorganization. Using the negative/deficit subtype, we detected genome-wide significant linkage to 1q23-25 (LOD = 3.78, empiric genome-wide P = .01). This region was not detected using the DSM-IV schizophrenia diagnosis, but has been strongly implicated in schizophrenia pathogenesis by previous linkage and association studies.Variants in the 1q region may specifically increase risk for a negative/deficit schizophrenia subtype. Alternatively, these results may reflect increased familiality/heritability of the negative class, the presence of multiple 1q schizophrenia risk genes, or a pleiotropic 1q risk locus or loci, with stronger genotype-phenotype correlation with negative/deficit symptoms. Using the second familial latent class, we identified nominally significant linkage to the original 10q peak region. Conclusion: Genetic analyses of heritable, homogeneous phenotypes may improve the power of linkage and association studies of schizophrenia and thus have relevance to the design and analysis of genome-wide association studies.

Molecular genetics and evolution of Puumala hantavirus

Puumala virus (PUUV) is the causative agent of nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome. Finland has the highest documented incidence of NE with around 1000 cases diagnosed annually. PUUV is also found in other Scandinavian countries, Central Europe and the European part of Russia. PUUV belongs to the genus Hantavirus in the family Bunyaviridae. Hantaviruses are rodent-borne viruses each carried by a specific host that is persistently and asymptomatically infected by the virus. PUUV is carried by the bank voles (Myodes glareolus, previously known as Clethrionomys glareolus). Hantaviruses have co-evolved with their carrier rodents for millions of years and these host animals are the evolutionary scene of hantaviruses. In this study, PUUV sequences were recovered from bank voles captured in Denmark and Russian Karelia to study the evolution of PUUV in Scandinavia. Phylogenetic analysis of these strains showed a geographical clustering of genetic variants following the presumable migration pattern of bank voles during the recolonization of Scandinavia after the last ice age approximately 10 000 years ago. The currently known PUUV genome sequences were subjected to in-depth phylogenetic analyses and the results showed that genetic drift seems to be the major mechanism of PUUV evolution. In general, PUUV seems to evolve quite slowly following a molecular clock. We also found evidence for recombination in the evolution of some genetic lineages of PUUV. Viral microevolution was studied in controlled virus transmission in colonized bank voles and changes in quasispecies dynamics were recorded as the virus was transmitted from one animal to another. We witnessed PUUV evolution in vivo, as one synonymous mutation became repeatedly fixed in the viral genome during the experiment. The detailed knowledge on the PUUV diversity was used to establish new sensitive and specific detection methods for this virus. Direct viral invasion of the hypophysis was demonstrated for the first time in a lethal case of NE. PUUV detection was done by immunohistochemistry, in situ hybridization and RT-nested-PCR of the autopsy tissue samples.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Genome-wide linkage analysis of multiple measures of neuroticism of 2 large cohorts from Australia and the Netherlands

CONTEXT People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the etiology of these important psychiatric disorders. OBJECTIVES To undertake a comprehensive genome-wide linkage study of neuroticism using large study samples that have been measured multiple times and to compare the results between countries for replication and across time within countries for consistency. DESIGN Genome-wide linkage scan. SETTING Twin individuals and their family members from Australia and the Netherlands. PARTICIPANTS Nineteen thousand six hundred thirty-five sibling pairs completed self-report questionnaires for neuroticism up to 5 times over a period of up to 22 years. Five thousand sixty-nine sibling pairs were genotyped with microsatellite markers. METHODS Nonparametric linkage analyses were conducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time-specific measures of neuroticism from each country to investigate consistency of linkage results. RESULTS Three chromosomal regions exceeded empirically derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 Kosambi cM (cM) (Dutch study sample), 14q 103 cM (Dutch study sample), and 18q 117 cM (combined Australian and Dutch study sample), but only 14q retained significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and 1 (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice. CONCLUSIONS Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbor causal variants for neuroticism and its related psychiatric disorders and can inform prioritization of results from genome-wide association studies.

Within-family outliers: Segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs

Most information in linkage analysis for quantitative traits comes from pairs of relatives that are phenotypically most discordant or concordant. Confounding this, within-family outliers from non-genetic causes may create false positives and negatives. We investigated the influence of within-family outliers empirically, using one of the largest genome-wide linkage scans for height. The subjects were drawn from Australian twin cohorts consisting of 8447 individuals in 2861 families, providing a total of 5815 possible pairs of siblings in sibships. A variance component linkage analysis was performed, either including or excluding the within-family outliers. Using the entire dataset, the largest LOD scores were on chromosome 15q (LOD 2.3) and 11q (1.5). Excluding within-family outliers increased the LOD score for most regions, but the LOD score on chromosome 15 decreased from 2.3 to 1.2, suggesting that the outliers may create false negatives and false positives, although rare alleles of large effect may also be an explanation. Several regions suggestive of linkage to height were found after removing the outliers, including 1q23.1 (2.0), 3q22.1 (1.9) and 5q32 (2.3). We conclude that the investigation of the effect of within-family outliers, which is usually neglected, should be a standard quality control measure in linkage analysis for complex traits and may reduce the noise for the search of common variants of modest effect size as well as help identify rare variants of large effect and clinical significance. We suggest that the effect of within-family outliers deserves further investigation via theoretical and simulation studies.

Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities

Latent class and genetic analyses were used to identify subgroups of migraine sufferers in a community sample of 6,265 Australian twins (55% female) aged 25-36 who had completed an interview based on International Headache Society (IHS) criteria. Consistent with prevalence rates from other population-based studies, 703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent class analysis (LCA) of IHS symptoms identified three major symptomatic classes, representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately severe form of migraine, typically without visual aura symptoms (although 40% of individuals in this class were positive for aura), and 3) a severe form of migraine typically with visual aura symptoms (although 24% of individuals were negative for aura). Using the LCA classification, many more individuals were considered affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic contribution to migraine using the LCA classification (heritability, h(2)=0.40; 95% CI, 0.29-0.46) compared with the IHS classification (h(2)=0.36; 95% CI, 0.22-0.42). Exploratory latent class modeling, fitting up to 10 classes, did not identify classes corresponding to either the IHS MO or MA classification. Our data indicate the existence of a continuum of severity, with MA more severe but not etiologically distinct from MO. In searching for predisposing genes, we should therefore expect to find some genes that may underlie all major recurrent headache subtypes, with modifying genetic or environmental factors that may lead to differential expression of the liability for migraine.