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author:("busan, Maja")
1.  A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder 
Human Molecular Genetics  2014;23(23):6395-6406.
We conducted blinded psychiatric assessments of 26 Amish subjects (52 ± 11 years) from four families with prevalent bipolar spectrum disorder, identified 10 potentially pathogenic alleles by exome sequencing, tested association of these alleles with clinical diagnoses in the larger Amish Study of Major Affective Disorder (ASMAD) cohort, and studied mutant potassium channels in neurons. Fourteen of 26 Amish had bipolar spectrum disorder. The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7 (c.1181G>A, p.Arg394His). KCNH7 c.1181G>A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (χ2 = 7.3) and the strongest family-based association with bipolar 1 (P = 0.021), bipolar spectrum (P = 0.031) and any major affective disorder (P = 0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder. Such a finding, if corroborated by future studies, has implications for mental health services among the Amish, as well as development of drugs that specifically target HERG3/Kv11.3.
PMCID: PMC4222358  PMID: 24986916
Rab3A is a small GTPase associated with synaptic vesicles that is required for some forms of activity-dependent plasticity. It is thought to regulate the number of vesicles that fuse through an effect on docking, vesicle maturation, or mobilization. We recently showed that at the neuromuscular junction, loss of Rab3A led to an increase in the occurrence of miniature endplate currents (mepcs) with abnormally long half widths (Wang et al., 2008). Here we show that such events are also increased after short-term activity blockade, and this process is not Rab3A-dependent. However, in the course of these experiments we discovered that the homeostatic increase in mepc amplitude after activity blockade is diminished in the Rab3A deletion mouse and abolished in the Rab3A Earlybird mouse which expresses a point mutant of Rab3A. We show that homeostatic plasticity at the neuromuscular junction does not depend on TNFα, is not accompanied by an increase in the levels of VAChT, the vesicular transporter for ACh, and confirm that there is no increase in ACh receptors at the junction, three characteristics distinct from that of central nervous system homeostatic plasticity. Activity blockade does not produce time course changes in mepcs that would be consistent with a fusion pore mechanism. We conclude that Rab3A is involved in a novel presynaptic mechanism to homeostatically regulate the amount of transmitter in a quantum.
PMCID: PMC3072228  PMID: 21389214
synaptic plasticity; synaptic vesicle release; presynaptic mechanisms; MEPP; knockout mice; TNFα
3.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
PMCID: PMC2943511  PMID: 19404256
4.  Population-based study of genetic variation in individuals with autism spectrum disorders from Croatia 
BMC Medical Genetics  2010;11:134.
Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis.
As a first step in the genetic analysis of ASD in Croatia, we characterized genetic variation in a sample of 103 subjects with ASD and 203 control individuals, who were genotyped using the Illumina HumanHap550 BeadChip. We analyzed the genetic diversity of the Croatian population and its relationship to other populations, the degree of relatedness via Runs of Homozygosity (ROHs), and the distribution of large (>500 Kb) copy number variations.
Combining the Croatian cohort with several previously published populations in the FastME analysis (an alternative to Neighbor Joining) revealed that Croatian subjects cluster, as expected, with Southern Europeans; in addition, individuals from the same geographic region within Europe cluster together. Whereas Croatian subjects could be separated from a sample of healthy control subjects of European origin from North America, Croatian ASD cases and controls are well mixed. A comparison of runs of homozygosity indicated that the number and the median length of regions of homozygosity are higher for ASD subjects than for controls (p = 6 × 10-3). Furthermore, analysis of copy number variants found a higher frequency of large chromosomal rearrangements (>2 Mb) in ASD cases (5/103) than in ethnically matched control subjects (1/197, p = 0.019).
Our findings illustrate the remarkable utility of high-density genotype data for subjects from a limited geographic area in dissecting genetic heterogeneity with respect to population and disease related variation.
PMCID: PMC2954843  PMID: 20858243
5.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
PMCID: PMC2925224  PMID: 19404257
6.  Emotional response in dopamine D2L receptor-deficient mice 
Behavioural brain research  2008;195(2):246-250.
The dopamine D2 receptor (D2R) system has been implicated in emotional processing which is often impaired in neuropsychiatric disorders. The long (D2L) and the short (D2S) isoforms of D2R are generated by alternative splicing of the same gene. To study differential roles of the two D2R isoforms, D2L-deficient mice (D2L−/−) expressing functional D2S were previously generated. In this study the contribution of D2L isoform to emotional response was investigated by examining behaviors that reflect emotionality (exploratory behavior, anxiety-like behavior and learned helplessness) in D2L−/− and (wild-type) WT mice. While the thigmotactic, locomotor and general components of anxiety in zero maze did not differ among the genotypes, D2L−/− mice displayed significantly lower level of exploration in a hole board and zero maze, and significantly higher increase in latency to escape from a foot shock after the learned helplessness training, compared with WT mice. These results suggest that D2L may play a more prominent role than D2S in mediating emotional response, such as behavioral reactions to novelty and inescapable stress. Our findings contribute to a better understanding of the molecular and cellular mechanisms underlying emotional responses.
PMCID: PMC2670426  PMID: 18835570
dopamine; D2L knockout mice; emotionality; anxiety; hole board; learned helplessness
7.  The Knockout Mouse Project 
Nature genetics  2004;36(9):921-924.
Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.
PMCID: PMC2716027  PMID: 15340423
8.  Motifs and cis-regulatory modules mediating the expression of genes co-expressed in presynaptic neurons 
Genome Biology  2009;10(7):R72.
An integrative strategy of comparative genomics, experimental and computational approaches reveals aspects of a regulatory network controlling neuronal-specific expression in presynaptic neurons.
Hundreds of proteins modulate neurotransmitter release and synaptic plasticity during neuronal development and in response to synaptic activity. The expression of genes in the pre- and post-synaptic neurons is under stringent spatio-temporal control, but the mechanism underlying the neuronal expression of these genes remains largely unknown.
Using unbiased in vivo and in vitro screens, we characterized the cis elements regulating the Rab3A gene, which is expressed abundantly in presynaptic neurons. A set of identified regulatory elements of the Rab3A gene corresponded to the defined Rab3A multi-species conserved elements. In order to identify clusters of enriched transcription factor binding sites, for example, cis-regulatory modules, we analyzed intergenic multi-species conserved elements in the vicinity of nine presynaptic genes, including Rab3A, that are highly and specifically expressed in brain regions. Sixteen transcription factor binding motifs were over-represented in these multi-species conserved elements. Based on a combined occurrence for these enriched motifs, multi-species conserved elements in the vicinity of 107 previously identified presynaptic genes were scored and ranked. We then experimentally validated the scoring strategy by showing that 12 of 16 (75%) high-scoring multi-species conserved elements functioned as neuronal enhancers in a cell-based assay.
This work introduces an integrative strategy of comparative genomics, experimental, and computational approaches to reveal aspects of a regulatory network controlling neuronal-specific expression of genes in presynaptic neurons.
PMCID: PMC2728526  PMID: 19570198
9.  Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes 
PLoS Genetics  2009;5(6):e1000536.
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
Author Summary
Autism spectrum disorders (ASDs) are common neurodevelopmental syndromes with a strong genetic component. ASDs are characterized by disturbances in social behavior, impaired verbal and nonverbal communication, as well as repetitive behaviors and/or a restricted range of interests. To identify genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. To enrich for variants most likely to interfere with gene function, we restricted our analyses to deletions and gains encompassing exons. Of the many genomic regions highlighted, 27 were seen to harbor rare variants in cases and not controls, both in the first phase of our analysis, and also in an independent replication cohort comprised of 859 cases and 1,051 controls. More work in a larger number of individuals will be required to determine which of the rare alleles highlighted here are indeed related to the ASDs and how they act to shape risk.
PMCID: PMC2695001  PMID: 19557195
10.  Genomic Landscape of a Three-Generation Pedigree Segregating Affective Disorder 
PLoS ONE  2009;4(2):e4474.
Bipolar disorder (BPD) is a common psychiatric illness with a complex mode of inheritance. Besides traditional linkage and association studies, which require large sample sizes, analysis of common and rare chromosomal copy number variants (CNVs) in extended families may provide novel insights into the genetic susceptibility of complex disorders. Using the Illumina HumanHap550 BeadChip with over 550,000 SNP markers, we genotyped 46 individuals in a three-generation Old Order Amish pedigree with 19 affected (16 BPD and three major depression) and 27 unaffected subjects. Using the PennCNV algorithm, we identified 50 CNV regions that ranged in size from 12 to 885 kb and encompassed at least 10 single nucleotide polymorphisms (SNPs). Of 19 well characterized CNV regions that were available for combined genotype-expression analysis 11 (58%) were associated with expression changes of genes within, partially within or near these CNV regions in fibroblasts or lymphoblastoid cell lines at a nominal P value <0.05. To further investigate the mode of inheritance of CNVs in the large pedigree, we analyzed a set of four CNVs, located at 6q27, 9q21.11, 12p13.31 and 15q11, all of which were enriched in subjects with affective disorders. We additionally show that these variants affect the expression of neuronal genes within or near the rearrangement. Our analysis suggests that family based studies of the combined effect of common and rare CNVs at many loci may represent a useful approach in the genetic analysis of disease susceptibility of mental disorders.
PMCID: PMC2637422  PMID: 19214233
11.  Modeling genetic inheritance of copy number variations 
Nucleic Acids Research  2008;36(21):e138.
Copy number variations (CNVs) are being used as genetic markers or functional candidates in gene-mapping studies. However, unlike single nucleotide polymorphism or microsatellite genotyping techniques, most CNV detection methods are limited to detecting total copy numbers, rather than copy number in each of the two homologous chromosomes. To address this issue, we developed a statistical framework for intensity-based CNV detection platforms using family data. Our algorithm identifies CNVs for a family simultaneously, thus avoiding the generation of calls with Mendelian inconsistency while maintaining the ability to detect de novo CNVs. Applications to simulated data and real data indicate that our method significantly improves both call rates and accuracy of boundary inference, compared to existing approaches. We further illustrate the use of Mendelian inheritance to infer SNP allele compositions in each of the two homologous chromosomes in CNV regions using real data. Finally, we applied our method to a set of families genotyped using both the Illumina HumanHap550 and Affymetrix genome-wide 5.0 arrays to demonstrate its performance on both inherited and de novo CNVs. In conclusion, our method produces accurate CNV calls, gives probabilistic estimates of CNV transmission and builds a solid foundation for the development of linkage and association tests utilizing CNVs.
PMCID: PMC2588508  PMID: 18832372
12.  Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms 
Nucleic Acids Research  2008;36(19):e126.
Whole-genome microarrays with large-insert clones designed to determine DNA copy number often show variation in hybridization intensity that is related to the genomic position of the clones. We found these ‘genomic waves’ to be present in Illumina and Affymetrix SNP genotyping arrays, confirming that they are not platform-specific. The causes of genomic waves are not well-understood, and they may prevent accurate inference of copy number variations (CNVs). By measuring DNA concentration for 1444 samples and by genotyping the same sample multiple times with varying DNA quantity, we demonstrated that DNA quantity correlates with the magnitude of waves. We further showed that wavy signal patterns correlate best with GC content, among multiple genomic features considered. To measure the magnitude of waves, we proposed a GC-wave factor (GCWF) measure, which is a reliable predictor of DNA quantity (correlation coefficient = 0.994 based on samples with serial dilution). Finally, we developed a computational approach by fitting regression models with GC content included as a predictor variable, and we show that this approach improves the accuracy of CNV detection. With the wide application of whole-genome SNP genotyping techniques, our wave adjustment method will be important for taking full advantage of genotyped samples for CNV analysis.
PMCID: PMC2577347  PMID: 18784189
13.  Genome-wide expression profiling and bioinformatics analysis of diurnally regulated genes in the mouse prefrontal cortex 
Genome Biology  2007;8(11):R247.
Microarray analysis shows that approximately 10% of transcripts in the mouse prefrontal cortex have diurnally regulated expression patterns.
The prefrontal cortex is important in regulating sleep and mood. Diurnally regulated genes in the prefrontal cortex may be controlled by the circadian system, by sleep:wake states, or by cellular metabolism or environmental responses. Bioinformatics analysis of these genes will provide insights into a wide-range of pathways that are involved in the pathophysiology of sleep disorders and psychiatric disorders with sleep disturbances.
We examined gene expression in the mouse prefrontal cortex at four time points during a 24 hour (12 hour light:12 hour dark) cycle using microarrays, and identified 3,890 transcripts corresponding to 2,927 genes with diurnally regulated expression patterns. We show that 16% of the genes identified in our study are orthologs of identified clock, clock controlled or sleep/wakefulness induced genes in the mouse liver and suprachiasmatic nucleus, rat cortex and cerebellum, or Drosophila head. The diurnal expression patterns were confirmed for 16 out of 18 genes in an independent set of RNA samples. The diurnal genes fall into eight temporal categories with distinct functional attributes, as assessed by Gene Ontology classification and analysis of enriched transcription factor binding sites.
Our analysis demonstrates that approximately 10% of transcripts have diurnally regulated expression patterns in the mouse prefrontal cortex. Functional annotation of these genes will be important for the selection of candidate genes for behavioral mutants in the mouse and for genetic studies of disorders associated with anomalies in the sleep:wake cycle and circadian rhythm.
PMCID: PMC2258187  PMID: 18028544
14.  Promoter features related to tissue specificity as measured by Shannon entropy 
Genome Biology  2005;6(4):R33.
A genome-wide analysis of promoters was carried out in the context of gene expression patterns in tissue surveys using human microarray and EST-based expression data. The study revealed that most genes show statistically significant tissue-dependent variations of expression level and identified components of promoters that distinguish tissue-specific from ubiquitous genes.
The regulatory mechanisms underlying tissue specificity are a crucial part of the development and maintenance of multicellular organisms. A genome-wide analysis of promoters in the context of gene-expression patterns in tissue surveys provides a means of identifying the general principles for these mechanisms.
We introduce a definition of tissue specificity based on Shannon entropy to rank human genes according to their overall tissue specificity and by their specificity to particular tissues. We apply our definition to microarray-based and expressed sequence tag (EST)-based expression data for human genes and use similar data for mouse genes to validate our results. We show that most genes show statistically significant tissue-dependent variations in expression level. We find that the most tissue-specific genes typically have a TATA box, no CpG island, and often code for extracellular proteins. As expected, CpG islands are found in most of the least tissue-specific genes, which often code for proteins located in the nucleus or mitochondrion. The class of genes with no CpG island or TATA box are the most common mid-specificity genes and commonly code for proteins located in a membrane. Sp1 was found to be a weak indicator of less-specific expression. YY1 binding sites, either as initiators or as downstream sites, were strongly associated with the least-specific genes.
We have begun to understand the components of promoters that distinguish tissue-specific from ubiquitous genes, to identify associations that can predict the broad class of gene expression from sequence data alone.
PMCID: PMC1088961  PMID: 15833120
15.  A Sperm-Associated WD Repeat Protein Orthologous to Chlamydomonas PF20 Associates with Spag6, the Mammalian Orthologue of Chlamydomonas PF16 
Molecular and Cellular Biology  2002;22(22):7993-8004.
cDNAs were cloned for the murine and human orthologues of Chlamydomonas PF20, a component of the alga axoneme central apparatus that is required for flagellar motility. The mammalian genes encode transcripts of 1.4 and 2.5 kb that are highly expressed in testis. The two transcripts appear to arise from alternative transcription start sites. The murine Pf20 gene was mapped to chromosome 1, syntenic with the location of the human gene on chromosome 2. An antibody generated against an N-terminal sequence of mouse Pf20 recognized a 71-kDa protein in sperm and testis extracts. Immunocytochemistry localized Pf20 to the tails of permeabilized sperm; electron microscope immunocytochemistry showed that Pf20 was located in the axoneme central apparatus. A murine Pf20-green fluorescent protein fusion protein expressed in Chinese hamster ovary cells accumulated in the cytoplasm. When coexpressed with Spag6, the mammalian orthologue of Chlamydomonas PF16, Pf20 was colocalized with Spag6 on polymerized microtubules. Yeast two-hybrid assays demonstrated interaction of the Pf20 WD repeats with Spag6. Pf20 was markedly reduced in sperm collected from mice lacking Spag6, which are infertile due to a motility defect. Our observations provide the first evidence for an association between mammalian orthologues of two Chlamydomonas proteins known to be critical for axoneme structure and function.
PMCID: PMC134734  PMID: 12391165
16.  Mapping autism risk loci using genetic linkage and chromosomal rearrangements 
Szatmari, Peter | Paterson, Andrew | Zwaigenbaum, Lonnie | Roberts, Wendy | Brian, Jessica | Liu, Xiao-Qing | Vincent, John | Skaug, Jennifer | Thompson, Ann | Senman, Lili | Feuk, Lars | Qian, Cheng | Bryson, Susan | Jones, Marshall | Marshall, Christian | Scherer, Stephen | Vieland, Veronica | Bartlett, Christopher | Mangin, La Vonne | Goedken, Rhinda | Segre, Alberto | Pericak-Vance, Margaret | Cuccaro, Michael | Gilbert, John | Wright, Harry | Abramson, Ruth | Betancur, Catalina | Bourgeron, Thomas | Gillberg, Christopher | Leboyer, Marion | Buxbaum, Joseph | Davis, Kenneth | Hollander, Eric | Silverman, Jeremy | Hallmayer, Joachim | Lotspeich, Linda | Sutcliffe, James | Haines, Jonathan | Folstein, Susan | Piven, Joseph | Wassink, Thomas | Sheffield, Val | Geschwind, Daniel | Bucan, Maja | Brown, Ted | Cantor, Rita | Constantino, John | Gilliam, Conrad | Herbert, Martha | Lajonchere, Clara | Ledbetter, David | Lese-Martin, Christa | Miller, Janet | Nelson, Stan | Samango-Sprouse, Carol | Spence, Sarah | State, Matthew | Tanzi, Rudolph | Coon, Hilary | Dawson, Geraldine | Devlin, Bernie | Estes, Annette | Flodman, Pamela | Klei, Lambertus | Mcmahon, William | Minshew, Nancy | Munson, Jeff | Korvatska, Elena | Rodier, Patricia | Schellenberg, Gerard | Smith, Moyra | Spence, Anne | Stodgell, Chris | Tepper, Ping Guo | Wijsman, Ellen | Yu, Chang-En | Rogé, Bernadette | Mantoulan, Carine | Wittemeyer, Kerstin | Poustka, Annemarie | Felder, Bärbel | Klauck, Sabine | Schuster, Claudia | Poustka, Fritz | Bölte, Sven | Feineis-Matthews, Sabine | Herbrecht, Evelyn | Schmötzer, Gabi | Tsiantis, John | Papanikolaou, Katerina | Maestrini, Elena | Bacchelli, Elena | Blasi, Francesca | Carone, Simona | Toma, Claudio | Van Engeland, Herman | De Jonge, Maretha | Kemner, Chantal | Koop, Frederieke | Langemeijer, Marjolein | Hijmans, Channa | Staal, Wouter | Baird, Gillian | Bolton, Patrick | Rutter, Michael | Weisblatt, Emma | Green, Jonathan | Aldred, Catherine | Wilkinson, Julie-Anne | Pickles, Andrew | Le Couteur, Ann | Berney, Tom | Mcconachie, Helen | Bailey, Anthony | Francis, Kostas | Honeyman, Gemma | Hutchinson, Aislinn | Parr, Jeremy | Wallace, Simon | Monaco, Anthony | Barnby, Gabrielle | Kobayashi, Kazuhiro | Lamb, Janine | Sousa, Ines | Sykes, Nuala | Cook, Edwin | Guter, Stephen | Leventhal, Bennett | Salt, Jeff | Lord, Catherine | Corsello, Christina | Hus, Vanessa | Weeks, Daniel | Volkmar, Fred | Tauber, Maïté | Fombonne, Eric | Shih, Andy | Meyer, Kacie
Nature Genetics  2007;39(3):319-328.
Autism spectrum disorders (ASD) are common, heritable neurodevelopmental conditions. The genetic architecture of ASD is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASD by using Affymetrix 10K single nucleotide polymorphism (SNP) arrays and 1168 families with ≥ 2 affected individuals to perform the largest linkage scan to date, while also analyzing copy number variation (CNV) in these families. Linkage and CNV analyses implicate chromosome 11p12-p13 and neurexins, respectively, amongst other candidate loci. Neurexins team with previously-implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for ASD.
PMCID: PMC4867008  PMID: 17322880
Chromosome Aberrations; Lod Score; Genetic Testing; Genetic Variation; Humans; Male; Risk Factors; Autistic Disorder; Chromosome Mapping; Family; Female; Genetic Linkage; Genetic Predisposition to Disease

Results 1-16 (16)