Janine A. Lamb

A Whole-Genome Scan and Fine-Mapping Linkage Study of Auditory-Visual Synesthesia Reveals Evidence of Linkage to Chromosomes 2q24, 5q33, 6p12, and 12p12

Synesthesia, a neurological condition affecting between 0.05%-1% of the population, is characterized by anomalous sensory perception and associated alterations in cognitive function due to interference from synesthetic percepts. A stimulus in one sensory modality triggers an automatic, consistent response in either another modality or a different aspect of the same modality. Familiality studies show evidence of a strong genetic predisposition; whereas initial pedigree analyses supported a single-gene X-linked dominant mode of inheritance with a skewed F:M ratio and a notable absence of male-to-male transmission, subsequent analyses in larger samples indicated that the mode of inheritance was likely to be more complex. Here, we report the results of a whole-genome linkage scan for auditory-visual synesthesia with 410 microsatellite markers at 9.05 cM density in 43 multiplex families (n = 196) with potential candidate regions fine-mapped at 5 cM density. Using NPL and HLOD analysis, we identified four candidate regions. Significant linkage at the genome-wide level was detected to chromosome 2q24 (HLOD = 3.025, empirical genome-wide p = 0.047). Suggestive linkage was found to chromosomes 5q33, 6p12, and 12p12. No support was found for linkage to the X chromosome; furthermore, we have identified two confirmed cases of male-to-male transmission of synesthesia. Our results demonstrate that auditory-visual synesthesia is likely to be an oligogenic disorder subject to multiple modes of inheritance and locus heterogeneity. This study comprises a significant step toward identifying the genetic substrates underlying synesthesia, with important implications for our understanding of the role of genes in human cognition and perception.

Risk for Myasthenia Gravis Maps to a (151)Pro -> Ala Change in TNIP1 and to Human Leukocyte Antigen-B*08

The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG).

MET and autism susceptibility: family and case-control studies.

Autism is a common, severe and highly heritable neurodevelopmental disorder. The International Molecular Genetic Study of Autism Consortium (IMGSAC) genome screen for linkage in affected sib-pair families identified a chromosome 7q susceptibility locus (AUTS1), that has subsequently shown evidence of increased sharing in several independent multiplex samples and in two meta-analyses. Taking into account the location of the MET gene under this linkage peak, and the fact that it has recently been reported to be associated with autism, the gene was further analyzed as a promising autism candidate. The gene encodes a transmembrane receptor tyrosine kinase of the hepatocyte growth factor/scatter factor (HGF/SF). MET is best known as an oncogene, but its signalling also participates in immune function, peripheral organ development and repair, and the development of the cerebral cortex and cerebellum (all of which have been observed earlier as being disregulated in individuals with autism). Here we present a family-based association analysis covering the entire MET locus. Significant results were obtained in both single locus and haplotype approaches with a single nucleotide polymorphism in intron 1 (rs38845, P<0.004) and with one intronic haplotype (AAGTG, P<0.009) in 325 multiplex IMGSAC families and 10 IMGSAC trios. Although these results failed to replicate in an independent sample of 82 Italian trios, the association itself was confirmed by a case–control analysis performed using the Italian cohort (P<0.02). The previously reported positive association of rs1858830 failed to replicate in this study. Overall, our findings provide further evidence that MET may play a role in autism susceptibility.

Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders

OBJECTIVE To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. CONCLUSION Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Mutation screening and association analysis of six candidate genes for autism on chromosome 7q.

Genetic studies have provided evidence for an autism susceptibility locus (AUTS1) on chromosome 7q. Screening for mutations in six genes mapping to 7q, CUTL1, SRPK2, SYPL, LAMB1, NRCAM and PTPRZ1 in 48 unrelated individuals with autism led to the identification of several new coding variants in the genes CUTL1, LAMB1 and PTPRZ1. Analysis of genetic variants provided evidence for association with autism for one of the new missense changes identified in LAMB1; this effect was stronger in a subgroup of affected male sibling pair families, implying a possible specific sex-related effect for this variant. Association was also detected for several polymorphisms in the promoter and untranslated region of NRCAM, suggesting that alterations in expression of this gene may be linked to autism susceptibility.

Bias in microRNA functional enrichment analysis

Motivation: Many studies have investigated the differential expression of microRNAs (miRNAs) in disease states and between different treatments, tissues and developmental stages. Given a list of perturbed miRNAs, it is common to predict the shared pathways on which they act. The standard test for functional enrichment typically yields dozens of significantly enriched functional categories, many of which appear frequently in the analysis of apparently unrelated diseases and conditions. Results: We show that the most commonly used functional enrichment test is inappropriate for the analysis of sets of genes targeted by miRNAs. The hypergeometric distribution used by the standard method consistently results in significant P-values for functional enrichment for targets of randomly selected miRNAs, reflecting an underlying bias in the predicted gene targets of miRNAs as a whole. We developed an algorithm to measure enrichment using an empirical sampling approach, and applied this in a reanalysis of the gene ontology classes of targets of miRNA lists from 44 published studies. The vast majority of the miRNA target sets were not significantly enriched in any functional category after correction for bias. We therefore argue against continued use of the standard functional enrichment method for miRNA targets. Availability and implementation: A Python script implementing the empirical algorithm is freely available at http://sgjlab.org/empirical-go/. Contact: sam.griffiths-jones@manchester.ac.uk or janine.lamb@manchester.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Autism: the quest for the genes

Autism, at its most extreme, is a severe neurodevelopmental disorder, and recent studies have indicated that autism spectrum disorders are considerably more common than previously supposed. However, although one of the most heritable neuropsychiatric syndromes, autism has so far eluded attempts to discover its genetic origins in the majority of cases. Several whole-genome scans for autism-susceptibility loci have identified specific chromosomal regions, but the results have been inconclusive and fine mapping and association studies have failed to identify the underlying genes. Recent advances in knowledge from the Human Genome and HapMap Projects, and progress in technology and bioinformatic resources, have aided study design and made data generation more efficient and cost-effective. Broadening horizons about the landscape of structural genetic variation and the field of epigenetics are indicating new possible mechanisms underlying autism aetiology, while endophenotypes are being used in an attempt to break down the complexity of the syndrome and refine genetic data. Although the genetic variants underlying idiopathic autism have proven elusive so far, the future for this field looks promising.

The Protein Tyrosine Phosphatase N22 Gene Is Associated With Juvenile and Adult Idiopathic Inflammatory Myopathy Independent of the HLA 8.1 Haplotype in British Caucasian Patients

OBJECTIVE To examine single-nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase N22 gene (PTPN22) and to study the relationship between PTPN22 and the HLA region in patients with idiopathic inflammatory myopathies (IIMs). METHODS PTPN22 SNPs were assessed in a large, cross-sectional, case-control study from the UK involving patients with adult or juvenile IIM, comprising patients with polymyositis (PM) (n=114), dermatomyositis (DM) (n=102), myositis associated with another connective tissue disease (myositis-CTD overlap syndrome) (n=64), or juvenile DM (n=101), in comparison with 748 control subjects. Seventeen PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis-specific/myositis-associated autoantibodies (MSAs/MAAs) was performed by radioimmunoprecipitation. RESULTS A significant association was noted between the R620W variant (rs2476601) and IIM (corrected P [Pcorr]=0.0009 versus controls), and specifically with the clinical subgroup of PM (Pcorr=0.003 versus controls). A weaker association was noted with juvenile DM (Pcorr=0.009 versus controls). No significant associations were noted after stratification by serologic subgroups. The association with the R620W variant was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM. CONCLUSION The R620W variant is a significant risk factor for IIM, independent of the HLA 8.1 haplotype. Unlike that in the HLA region, risk is not increased in individuals possessing MSAs/MAAs. These results are further evidence that the PTPN22 gene confers autoimmune susceptibility.

Disease specificity of autoantibodies to cytosolic 5'-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases

Objectives The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5′-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls. Methods Serum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs. Results Autoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (<5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sjögrens syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%). Conclusions In summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist.

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

Objectives The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. Results The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10−8). Nine regions were associated at a significance level of p<2.25×10−5, including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. Conclusions This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.