Association study of gender identity disorder and sex hormone-related genes

To investigate the biological mechanism of gender identity disorder (GID), five candidate sex hormone-related genes, encoding androgen receptor (AR), estrogen receptors α (ERα) and β (ERβ), aromatase (CYP19), and progesterone receptor (PGR) were analyzed by a case–control association study. Subjects were 242 transsexuals (74 male-to-female patients (MTF) and 168 female-to-male patients (FTM)), and 275 healthy age- and geographical origin-matched controls (106 males and 169 females). The distributions of CAG repeat numbers in exon 1 of AR, TA repeat numbers in the promoter region of ERα, CA repeat numbers in intron 5 of ERβ, TTTA repeat numbers in intron 4 of CYP19, and six polymorphisms (rs2008112, rs508653, V660L, H770H, rs572698 and PROGINS) of PGR were analyzed. No significant difference in allelic or genotypic distribution of any gene examined was found between MTFs and control males or between FTMs and control females. The present findings do not provide any evidence that genetic variants of sex hormone-related genes confer individual susceptibility to MTF or FTM transsexualism.     

Noisy galvanic vestibular stimulation: an emerging treatment option for bilateral vestibulopathy

Migraine is a common and disabling nervous system disease with a significant genetic predisposition. The sex hormones play an important role in the pathogenesis of migraine. However, the conclusions of the previous genetic relation studies are conflicting. The aim of this study is to determine whether variants in genes involved in estrogen receptor and estrogen hormone metabolism are related to Chinese migraine. By employing a case–control approach, 8 SNPs in the ESR1, ESR2, and CYP19A1 genes are studied in a cohort of 494 migraine cases and 533 controls. In addition, genotyping is performed using Sequenom MALDI-TOF mass spectrometry iPLEX platform. Univariate and multivariate analyses are carried out by logistic regression. The corresponding haplotypes are studied with the Haploview software and gene–gene interaction is assessed using the Generalized Multifactor Dimensionality Reduction (GMDR) analysis. There are significant differences in allelic distributions for rs2234693 and rs9340799 in ESR1 gene between patients with migraine and control subjects. Univariate logistic analysis shows that rs2234693 and rs9340799 are risk factors for migraine, but multivariate analysis reveals that only rs2234693 is significant associated with migraine. In the subgroup analysis, rs2234693 in ESR1 gene is found associated with menstrually related migraine. Further haplotypic analysis shows that rs2234693–rs9340799 TA haplotype serves as risk haplotype for migraine. The GMDR analysis identifies rs2234693 in ESR1 alone to be a crucial candidate in migraine susceptibility. This study is in agreement with the previous studies that variants in the ESR1 gene are associated with migraine suggesting that it plays a role in the migraine process.     

Association between migraine and a functional polymorphism at the dopamine β-hydroxylase locus

Migraine is a common neurological disorder with a significant genetic component. Although a number of linkage and association studies have been undertaken, the number and identity of all migraine susceptibility genes has yet to be defined. The existence of dopaminergic hypersensitivity in migraine has been recognised on a pharmacological basis and some studies have reported genetic association between migraine and dopamine-related gene variants. Our laboratory has previously reported association of migraine with a promoter STR marker in the dopamine beta hydroxylase (DBH) gene. In the present study, we analysed two additional DBH markers in two independent migraine case–control cohorts. These two markers are putative functional SNPs, one within the promoter (−1021C→T) and another SNP (+1603C→T) in exon 11 of the DBH gene. The results showed a significant association for allelic and genotypic frequency distribution between the DBH marker in the promoter and migraine in the first (P = 0.004 and P = 0.012, respectively) and the second (P = 0.013 and P = 0.031, respectively) tested cohorts. There was no association observed between either genotype and/or allelic frequencies for the DBH marker located in exon 11 and migraine (P ≥ 0.05). The promoter DBH marker, reported associated with migraine in this study, has been shown to affect up to 52% of plasma DBH activity. Varying DBH activity levels have been postulated to be involved in migraine process with an increase of dopamine, resulting from a lower DBH activity shown positively correlated with migraine severity. It is plausible that the functional promoter variant of DBH may play a role in the migraine disorder.     

Lack of association of hormone receptor polymorphisms with migraine

Background and purpose:  Previous studies concerning the role of hormone receptor genetic variants in migraine have provided conflicting results. The aim of this study was to investigate the role of common polymorphisms in the estrogen receptor gene ( ESR1 ) and the progesterone receptor gene ( PGR ) in the risk for migraine in a Spanish population.
Methods:  In a case–control study, including 210 Caucasoid migraine patients and 210 controls, we examined association between three single nucleotide polymorphisms in the coding region of ESR1 , rs2077642, rs1801132, and rs2228480, and an Alu insertion in PGR , and migraine, migraine without aura or migraine with aura. Genotypic, allelic and reconstructed haplotype distributions were compared.
Results:  We found no significant differences between cases and controls in the distribution of genotypes or alleles for either polymorphism. No haplotype was over-represented in patients.
Conclusions:  Our study does not support a major contribution of ESR1 and PGR to the pathogenesis of migraine.     

Examination of association of genes in the serotonin system to autism

Autism is characterized as one of the pervasive developmental disorders, a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-hydroxytryptamine) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 single nucleotide polymorphisms in ten serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p = 0.0002; p = 0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on chromosome 11 (∼113 Mb). To test specifically for multilocus effects, multifactor dimensionality reduction was employed, and a significant two-way interaction (p value = 0.01) was found between rs10830962, near MTNR1B (chromosome11; 92,338,075 bp), and rs1007631, near SLC7A5 (chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

LINGO1 polymorphisms are associated with essential tremor in Europeans

Essential tremor (ET) is one of the most common movement disorders. Former association studies focussing on candidate genes in ET found a number of risk variants but most of them were not replicated. Recently, a genome‐wide association study revealed two intronic sequence variants in the LINGO1 gene associated with ET. Here, we have confirmed association between sequence variants in the LINGO1 gene and the ET phenotype in independent German and French ET samples. The odds ratios for the identified intronic markers rs8030859 (P = 1.0×10^?4), rs9652490 (P = 9.1×10^?4), and rs11856808 (P = 3.6×10^?2) were 1.72 (CI 1.31‐2.26), 1.61 (CI 1.21‐2.14), and 1.30 (CI 1.02‐1.66), respectively, in our German sample. LINGO1 is an interesting candidate gene because it plays a key role in central nervous system biology, is selectively expressed in the nervous system, and is an inhibitor of oligodendrocyte differentiation and neuronal myelination. Our study gives further evidence that LINGO1 acts as a susceptibility gene for ET. © 2010 Movement Disorder Society     

Variants in estrogen‐related genes and risk of Parkinson's disease

Incidence rates of Parkinson's disease are higher in men than in women at all ages, and these differences may be a result of the neuroprotective effects of estrogen on the nigrostriatal pathway. We investigated the association of common variants in 4 estrogen‐related genes with Parkinson's disease. Tagging single‐nucleotide polymorphisms in the CYP19A1, ESR1, ESR2, and PRDM2 genes were selected from the International Haplotype Map and genotyped in 1103 Parkinson's disease cases from the upper Midwest of the United States and in 1103 individually matched controls (654 unaffected siblings, and 449 unrelated controls from the same region). Of 137 informative single‐nucleotide polymorphisms, 2 PRDM2 single‐nucleotide polymorphisms were significantly associated with an increased risk of Parkinson's disease at the Bonferroni‐corrected significance level of 0.0004 (rs2744690: OR, 1.54; SE(logOR), .109; 99.96% CI, 1.05–2.26; uncorrected P = .0001; rs2744687: OR, 1.53; SE(logOR), .113; 99.96% CI, 1.03–2.29, uncorrected P = .0002); the association was significant in the women‐only stratum but not in the men‐only stratum. An additional 6 single‐nucleotide polymorphisms in PRDM2, 2 in ESR1, 1 in ESR2, and 1 in CYP19A1 had significant P values in the overall sample before Bonferroni correction. None of the single‐nucleotide polymorphisms were significantly associated with age at onset of Parkinson's disease after Bonferroni correction. Our results confirm the association of PRDM2 variants with Parkinson's disease susceptibility, especially in women. © 2011 Movement Disorder Society     

Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism

OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region. METHOD: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families. RESULTS: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci. CONCLUSIONS: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.     

Further examination of the candidate genes in chromosome 12p13 locus for late-onset Alzheimer disease

A broad region on chromosome 12p13 has been intensely investigated for novel genetic variants associated with Alzheimer disease (AD). We examined this region with 23 microsatellite markers using 124 North European (NE) families and 209 Caribbean Hispanic families with late-onset AD (FAD). Significant evidence for linkage was present in a 5-cM interval near 20 cM in both the NE FAD (LOD = 3.5) and the Caribbean Hispanic FAD (LOD = 2.2) datasets. We further investigated these families and an independent NE case–control dataset using 14 single nucleotide polymorphisms (SNPs). The initial screening of the region at ∼20 cM in the NE case–control dataset revealed significant association between AD and seven SNPs in several genes, with the strongest result for rs2532500 in TAPBPL (p = 0.006). For rs3741916 in GAPDH, the C allele, rather than the G allele as was observed by Li et al. (Proc Natl Acad Sci U S A 101(44):15688–15693, 2004), was the risk allele. When the two family datasets were examined, none of the SNPs were significant in NE families, but two SNPs were associated with AD in Caribbean Hispanics: rs740850 in NCAPD2 (p = 0.0097) and rs1060620 in GAPDH (p = 0.042). In a separate analysis combining the Caribbean Hispanic families and NE cases and controls, rs740850 was significant after correcting for multiple testing (empirical p = 0.0048). Subsequent haplotype analyses revealed that two haplotype sets—haplotype C-A at SNPs 6–7 within NCAPD2 in Caribbean Hispanics, and haplotypes containing C-A-T at SNPs 8–10 within GAPDH in Caribbean Hispanic family and NE case–control datasets—were associated with AD. Taken together, these SNPs may be in linkage disequilibrium with a pathogenic variant(s) on or near NCAPD2 and GAPDH. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

ARVCF single marker and haplotypic association with schizophrenia

We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3′ downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3′ region of the ARVCF gene.     

A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of ANK3 and additional rare alleles at 10q11-q21

BackgroundBipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness.MethodsOverall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder–manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a gene-based segregation test.ResultsWe identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LOD_exp] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies — or variants in linkage disequilibrium with those variants — did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014).LimitationsWe did not examine non-coding variants, but they may explain the remaining linkage signal.ConclusionCombining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.     

Nitric oxide synthase genes and their interactions with environmental factors in Parkinson’s disease

Nitric oxide synthase (NOS) genes (NOS1, NOS2A, and NOS3) may create excess nitric oxide that contributes to neurodegeneration in Parkinson’s disease (PD). NOS genes might also interact with one another or with environmental factors in PD. Coding and tagging single nucleotide polymorphisms (SNPs) (27 NOS1, 18 NOS2A, and five NOS3 SNPs) were genotyped in families with PD (1,065 cases and 1,180 relative and other controls) and were tested for allelic associations with PD using the association in the presence of linkage test and the pedigree disequilibrium test (PDT), allelic associations with age-at-onset (AAO) using the quantitative transmission disequilibrium test, and interactions using the multifactor dimensionality reduction—PDT. Gene–environment interactions involving cigarette smoking, caffeine, nonsteroidal anti-inflammatory drugs, and pesticides were examined using generalized estimating equations in participants with environmental data available. Significant associations with PD were detected for the NOS1 SNPs rs3782218, rs11068447, rs7295972, rs2293052, rs12829185, rs1047735, rs3741475, and rs2682826 (range of p = 0.00083–0.046) and the NOS2A SNPs rs2072324, rs944725, rs12944039, rs2248814, rs2297516, rs1060826, and rs2255929 (range of p = 0.0000040–0.047) in earlier-onset families with sporadic PD, and some SNPs were also associated with earlier AAO. There was no compelling statistical evidence for gene–gene interactions. However, of the significantly associated SNPs, interactions were found between pesticides and the NOS1 SNPs rs12829185, rs1047735, and rs2682826 (range of p = 0.012–0.034) and between smoking and the NOS2A SNPs rs2248814 (p = 0.021) and rs1060826 (p = 0.013). These data implicate NOS1 and NOS2A as genetic risk factors for PD and demonstrate that their interactions with established environmental factors may modulate the environmental effects.     

High‐density SNP screen of sodium channel genes by haplotype tagging and DNA pooling for association with idiopathic generalized epilepsy

We have investigated seven voltage‐gated sodium channel genes for association with idiopathic generalized epilepsy (IGE). Probands and control DNA were grouped into pools and used to screen 85 single‐nucleotide polymorphisms (SNPs), mostly HapMap SNPs tagging the common variation in these genes. Twelve SNPs exhibiting an allele frequency difference between pools were genotyped individually in our sample of 232 probands, 313 controls, and 95 parent–proband trios. Two SNPs, in SCN1A and SCN8A, were associated by allele and genotype at nominal level of significance, but were not significant after Bonferroni correction. Two SCN2A SNPs (rs3943809 and rs16850331) were associated by case–control with a subgroup with IGE and history of febrile seizures and also by transmission disequilibrium test (TDT) in parent–proband trios. Both SNPs are part of a linkage disequilibrium (LD) cluster of 38 SNPs, but none are obvious functional variants. The association of rs3943809 with the febrile seizure subgroup (p = 0.0004) remains significant after the conservative Bonferroni correction for multiple testing.     

An association analysis at 2q36 reveals a new candidate susceptibility gene for juvenile absence epilepsy and/or absence seizures associated with generalized tonic-clonic seizures

Purpose: To further evaluate the previously shown linkage of absence epilepsy (AE) to 2q36, both in human and WAG/Rij absence rat models, a 160‐kb region at 2q36 containing eight genes with expressions in the brain was targeted in a case–control association study involving 205 Turkish patients with AE and 219 controls. Methods: Haplotype block and case–control association analysis was carried out using HAPLOVIEW 4.0 and inhibin alpha subunit (INHA) gene analysis by DNA sequencing. Key Findings: An association was found between the G allele of rs7588807 located in the INHA gene and juvenile absence epilepsy (JAE) syndrome and patients having generalized tonic–clonic seizures (GTCS) with p‐values of 0.003 and 0.0002, respectively (uncorrected for multiple comparisons). DNA sequence analysis of the INHA gene in 110 JAE/GTCS patients revealed three point mutations with possible damaging effects on inhibin function in three patients and the presence of a common ACTC haplotype (H1) with a possible dominant protective role conferred by the T allele of rs7588807 with respective p‐values of 0.0005 and 0.0014. Significance: The preceding findings suggest that INHA could be a novel candidate susceptibility gene involved in the pathogenesis of JAE or AE associated with GTCS.     

The interleukin‐1 cluster gene region is associated with multiple sclerosis in an Italian Caucasian population

Background: Polymorphisms of the interleukin‐1 (IL‐1) gene family have been proposed as potential variants for different diseases including multiple sclerosis (MS). With respect to MS, IL‐1 beta (?511 C/T; rs16944), IL‐1 beta (+3954 C/T; rs1143634), IL‐1 alpha (?889 C/T; rs1800587), IL‐1 alpha (+4845 G/T; rs17561), and the variable number of tandem repeats in intron 2 of the IL‐1 receptor antagonist (IL‐1RN) gene polymorphisms have been studied in different ethnic groups, leading to conflicting results. Methods: This study investigates the association between IL‐1 genes and MS by means of 70 markers spanning the 1.1 Mb region where the IL‐1 genes map and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case–control design including 410 subjects (160 patients and 250 controls). Results: From allelic/genotypic tests, significant association was found for several polymorphisms including the IL‐1 beta (?511 C/T) variant (P‐adjusted = 4.5 × 10^?4) and some polymorphisms around the IL‐1RN gene. The ‘block‐step’ pattern obtained from both the LD map and pairwise analysis identifies four LD regions. Region 1 showed a significant association with MS for the global test (P < 0.0001) and haplotypes containing the IL‐1 beta (?511 C/T) variant still demonstrate highly significant association with disease (P‐value range: 9.9 × 10^?5 to 0.02). Conclusions: Our findings support the existence of a causative variant for MS within this candidate region in a representative Italian Caucasian population and, in particular, the role of the IL‐1 beta (?511 C/T) variant warrants further investigation.     

Identification of a Novel ANKK1 and Other Dopaminergic (DRD2 and DBH) Gene Variants in Migraine Susceptibility

The dopaminergic system plays an important role in migraine and its clinical subtypes. Hypersensitization of dopamine receptor type 2 (DRD2) in migraine led to successful administration of receptor antagonists in antimigraine therapy. Ankyrin repeats and kinase domain containing 1 (ANKK1) gene in DRD2 loci is linked to comorbid neurological disorders. Dopamine beta hydroxylase (DBH) is responsible for maintaining dopamine-to-norepinephrine ratio implicated in migraine pathophysiology. Therefore, we aimed to look for association of functional variants in ANKK1 (rs1800497), DRD2 (rs6275 and rs1799732) and DBH (rs7239728 and rs1611115) genes with migraine susceptibility. The present study was carried out in two dependent cohorts (n _primary = 208, n _secondary = 127, n _controls = 200). The results of the cohorts were pooled by meta-analysis using Fisher’s and Mantel–Haenszel test. Benjamini–Hochberg false discovery rate test was used to correct for multiple comparisons. Computer algorithm-based TANGO, WALTZ and LIMBO predictions were used to evaluate the effect of missense polymorphism (rs1800497). For ANKK1 polymorphism, variant genotype and allele showed significant associations with migraine risk. A significant protective effect of variant DRD2 rs6275 polymorphism was noticed. DBH rs7239728 imparted significant risk at genotypic, allelic and carrier analyses. We identified a risk haplotype in DRD2 loci. Two genotype interactions between ANKK1rs1800497 and DBHrs72393728 polymorphisms showed significant risks. The variant gene product of ANKK1 rs1800497 was predicted with decreased aggregation of ANKK1 protein. In conclusion, we identified novel genetic variants, haplotype and gene interactions in dopaminergic pathway as potential risk factors for migraine susceptibility.     

Investigation of hormone receptor genes in migraine

Migraine is a common neurological condition with a complex mode of inheritance. Steroid hormones have long been implicated in migraine, although their role remains unclear. Our investigation considered that genes involved in hormonal pathways may play a role in migraine susceptibility. We therefore investigated the androgen receptor (AR) CAG repeat, and the progesterone receptor (PR) PROGINS insert by cross-sectional association analysis. The results showed no association with the AR CAG repeat in our study group of 275 migraineurs and 275 unrelated controls. Results of the PR PROGINS analysis showed a significant difference in the same cohort, and in an independent follow-up study population of 300 migraineurs and 300 unrelated controls. Analysis of the genotypic risk groups of both populations together indicated that individuals who carried the PROGINS insert were 1.8 times more likely to suffer migraine. Interaction analysis of the PROGINS variant with our previously reported associated ESR1 594A variant showed that individuals who possessed at least one copy of both risk alleles were 3.2 times more likely to suffer migraine. Hence, variants of these steroid hormone receptor genes appear to act synergistically to increase the risk of migraine by a factor of three.     

Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response

GDNF (glial-cell-line derived neurotrophic factor) is a potent neurotrophic factor for dopaminergic neurons. Neuropsychiatric diseases and their treatments are associated with alterations in the levels of both GDNF and its receptor family (GDNF family receptor alpha or GFRA). GFRA1, GFRA2 and GFRA3 are located in chromosomal regions with suggestive linkage to schizophrenia. In this study we analyzed polymorphisms located in all four known GFRA genes and examined association with schizophrenia and clozapine response. We examined SNPs across the genes GFRA1-4 in 219 matched case-control subjects, 85 small nuclear families and 140 schizophrenia patients taking clozapine for 6 months. We observed that GFRA3 rs11242417 and GFRA1 rs11197557 variants were significantly associated with schizophrenia after combining results from both schizophrenia samples. Furthermore, we found an overtransmission of the G-C GFRA1 rs7920934-rs730357 haplotype to subjects with schizophrenia and association of A-T-G-G GFRA3 rs10036665-rs10952-rs11242417-rs7726580 with schizophrenia in the case-control sample. On the other hand, GFRA2 variants were not associated with schizophrenia diagnosis but subjects carrying T-G-G rs1128397-rs13250096-rs4567028 haplotype were more likely to respond to clozapine treatment. The statistical significance of results survived permutation testing but not Bonferroni correction. We also found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia.     

A typical migraine susceptibility region localizes to chromosome 1q31

Migraine (with and without aura) is a prevalent neurovascular disease that shows strong familial aggregation, although the number of genes involved and the mode of inheritance is not clear. Some insight into the disease has been gained from genetic studies into a rare and very severe migraine subtype known as familial hemiplegic migraine (FHM). In this study, we took a family-based linkage and association approach to investigate the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chr1q31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned approximately 18 cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782 (P=0.00004). Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P=0.008). Utilising the independent sample of 82 pedigrees, we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 [global χ² ₍₅₎ of 15.00, P=0.010] in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers. However, overall they provide good evidence for the existence of a typical migraine locus near these markers on Chr1q31, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine. Electronic Publication