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1.  On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis 
BMC Genomics  2014;15(1):368.
Background
As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation.
Results
The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p = 4.3×10−16) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p = 0.003, frequency = 16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR = 3.1, p = 0.009, frequency 1.2%) and 5q13.2 deletions (OR = 1.5, p = 0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p = 3.15×10−18).
Conclusion
Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-368) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-368
PMCID: PMC4035084  PMID: 24884913
Body mass index; Obesity; Genome-wide association; Copy number variation; Risk prediction; Polygenic score; FTO; MC4R
2.  A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53 
Molecular psychiatry  2012;18(11):10.1038/mp.2012.143.
Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with symptom count were also associated with the dichotomous phenotype, DSM-IV alcohol dependence. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol (p=4.5×10−8, inflation corrected p=9.4×10−7). Results with DSM-IV alcohol dependence in the regions of interest support our findings with symptom count, though the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: non-overlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian twin-family study of alcohol use disorders (OZALC). Nominal association of C15orf53 with symptom count was observed in SAGE. The variant that showed strongest association with symptom count, rs12912251 and its highly correlated variants (D′=1, r2≥ 0.95), has previously been associated with risk for bipolar disorder.
doi:10.1038/mp.2012.143
PMCID: PMC3752321  PMID: 23089632
DSM-IV alcohol dependence symptoms; Family-based GWAS; C15orf53; Quantitative traits
3.  Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders 
Molecular Autism  2014;5:28.
Background
Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study.
Methods
From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants.
Results
The ANXA1 duplication, overlapping the last four exons and 3’UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3’UTR identified 11 novel changes, but no obvious variants with clinical significance.
Conclusions
We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.
doi:10.1186/2040-2392-5-28
PMCID: PMC4098665  PMID: 24720851
ANXA1; Autism; Brain homeostasis; Copy number variants; Duplication; Glucocorticoids
4.  Genetic influences on craving for alcohol 
Addictive behaviors  2012;38(2):1501-1508.
Introduction
Craving is being considered for inclusion in the Diagnostic and Statistical Manual (DSM) DSM-5. However, little is known of its genetic underpinnings – specifically, whether genetic influences on craving are distinct from those influencing DSM-IV alcohol dependence.
Method
Analyses were conducted in a sample of unrelated adults ascertained for alcohol dependence (N=3976). Factor analysis was performed to examine how alcohol craving loaded with the existing DSM-IV alcohol dependence criteria. For genetic analyses, we first examined whether genes in the dopamine pathway, including dopamine receptor genes (DRD1, DRD2, DRD3, DRD4) and the dopamine transporter gene (SLC6A3), which have been implicated in neurobiological studies of craving, as well as alpha-synuclein (SNCA), which has been previously found to be associated with craving, were associated with alcohol craving in this sample. Second, in an effort to identify novel genetic variants associated with craving, we conducted a genomewide association study (GWAS). For variants that were implicated in the primary analysis of craving, we conducted additional comparisons - to determine if these variants were uniquely associated with alcohol craving as compared with alcohol dependence. We contrasted our results to those obtained for DSM-IV alcohol dependence, and also compared alcohol dependent individuals without craving to non-dependent individuals who also did not crave alcohol.
Results
Twenty-one percent of the full sample reported craving alcohol. Of those reporting craving, 97.3% met criteria for DSM-IV alcohol dependence with 48% endorsing all 7 dependence criteria. Factor analysis found a high factor loading (0.89) for alcohol craving. When examining genes in the dopamine pathway, single nucleotide polymorphisms (SNPs) in DRD3 and SNCA were associated with craving (p<0.05). There was evidence for association of these SNPs with DSM-IV alcohol dependence (p<0.05) but less evidence for dependence without craving (p>0.05), suggesting that the association was due in part to craving. In the GWAS, the greatest evidence of association with craving was for a SNP in the integrin alpha D (ITGAD) gene on chromosome 7 (rs2454908; p=1.8×10−6). The corresponding p-value for this SNP with DSM-IV alcohol dependence was similar (p=4.0×10−5) but was far less with dependence without craving (p=0.02), again suggesting the association was due to alcohol craving. Adjusting for dependence severity (number of endorsed criteria) attenuated p-values but did not eliminate association.
Conclusions
Craving is frequently reported by those who report multiple other alcohol dependence symptoms. We found that genes providing evidence of association with craving were also associated with alcohol dependence; however, these same SNPs were not associated with alcohol dependence in the absence of alcohol craving. These results suggest that there may be unique genetic factors affecting craving among those with alcohol dependence.
doi:10.1016/j.addbeh.2012.03.021
PMCID: PMC3394913  PMID: 22481050
5.  CHRNB3 is more strongly associated with FTCD-based nicotine dependence than cigarettes per day: phenotype definition changes GWAS results 
Addiction (Abingdon, England)  2012;107(11):2019-2028.
Aims
Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerström Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence.
Design
Genome-wide association study
Setting
Community sample
Participants
A total of 3,365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2,267 were European Americans,999 were African Americans.
Measurements
Nicotine dependence defined by FTCD score ≥4, CPD
Findings
The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 (OR=0.65, p=2.4×10−8). This association was further strengthened in a meta-analysis with a previously published dataset (combined p=6.7 ×10−16, total n=4,200).When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (β=−0.08, p=0.0007).
Conclusions
Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence (FTCD) show different associations with polymorphisms in genetic loci.
doi:10.1111/j.1360-0443.2012.03922.x
PMCID: PMC3427406  PMID: 22524403
6.  Sex differences in how a low sensitivity to alcohol relates to later heavy drinking 
Drug and alcohol review  2012;31(7):871-880.
Introduction and Aims
A low level of response (LR), or low sensitivity, to alcohol is a genetically-influenced characteristic that predicts future heavy drinking and alcohol problems. While previous analyses of how LR relates to heavier drinking reported the process is similar in males and females, some potential sex differences have been identified. This difference is further explored in these analyses.
Design and Methods
Prospective structural equation models (SEMs) were evaluated for 183 young adult females and 162 males, none of Asian background, from the Collaborative Study on the Genetics of Alcoholism (COGA). Invariance analyses and SEM evaluations by sex were used to compare across females and males for these primarily Caucasian (75%), non-Asian young (mean age 19) subjects.
Results
The prospective SEM for the full set of 345 subjects had good fit characteristics and explained 37% of the variance. While the initial invariance analyses identified few sex differences, comparisons of correlations and direct evaluations of path coefficients across males and females indicated that only females showed a link between a low LR and future alcohol problems that was partially mediated by more positive alcohol expectancies and drinking to cope. These sex differences were reflected in the different structures of the SEM results for female vs. male subjects.
Discussion and Conclusions
These prospective results indicate that there might be some important sex differences regarding how a lower LR relates to alcohol outcomes that should be considered in protocols focusing on preventing the impact of LR on future drinking problems.
doi:10.1111/j.1465-3362.2012.00469.x
PMCID: PMC3459074  PMID: 22708705
drinking; alcoholism; sex; genetics; structural equation models
7.  The aggregate effect of dopamine genes on dependence symptoms among cocaine users: Cross-validation of a candidate system scoring approach 
Behavior genetics  2012;42(4):626-635.
Genome-wide studies of psychiatric conditions frequently fail to explain a substantial proportion of variance, and replication of individual SNP effects is rare. We demonstrate a selective scoring approach, in which variants from several genes known to directly affect the dopamine system are considered concurrently to explain individual differences in cocaine dependence symptoms. 273 SNPs from eight dopamine-related genes were tested for association with cocaine dependence symptoms in an initial training sample. We identified a four-SNP score that accounted for 0.55% of the variance in a separate testing sample (p = 0.037). These findings suggest that 1) limiting investigated SNPs to those located in genes of theoretical importance improves the chances of identifying replicable effects by reducing statistical penalties for multiple testing, and 2) considering top-associated SNPs in the aggregate can reveal replicable effects that are too small to be identified at the level of individual SNPs.
doi:10.1007/s10519-012-9531-4
PMCID: PMC3416038  PMID: 22358648
candidate gene; cocaine dependence; dopamine
8.  Genome-wide association study of comorbid depressive syndrome and alcohol dependence 
Psychiatric genetics  2012;22(1):31-41.
Objective
Depression and alcohol dependence are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that alcohol dependence and depression are genetically correlated. Here we report results from a genome-wide association study (GWAS) of a comorbid phenotype in which cases meet the DSM-IV symptom threshold for major depressive symptomatology and DSM-IV criteria for alcohol dependence.
Methods
Samples (N=467 cases and N=407 controls) were of European-American descent, and were genotyped using the Illumina Human 1M BeadChip array.
Results
Although no SNP meets genome-wide significance criteria, we identify ten markers with p-values < 1 × 10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding p<1 × 10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, alcohol dependence, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an alcohol dependence-only phenotype is modest.
Conclusions
These results underscore the complex genomic influences on psychiatric phenotypes, and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect alcohol dependence alone.
doi:10.1097/YPG.0b013e32834acd07
PMCID: PMC3241912  PMID: 22064162
genetics of alcoholism; comorbidity; genetic risk; depressive syndrome
9.  Genome Wide Linkage Analysis of 972 Bipolar Pedigrees Using Single Nucleotide Polymorphisms 
Molecular Psychiatry  2011;17(8):818-826.
Because of the high costs associated with ascertainment of families most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. While microsatellite markers spaced every 10 centimorgans typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carry out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 SNPs. Of the ~1100 families, 972 were informative for further analyses and mean information content was 0.86 after pruning for LD. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with Bipolar II disorder (BPII) and 702 subjects with Recurrent Major Depression. Three affection status models were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus Recurrent Major Depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (Nonparametric Pairs Lod 3.4 for rs1046943 at 119 cM) and 9q21 (Nonparametric Pairs Lod 3.4 for rs722642 at 78 cM) using only BPI and SA, BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis we observed 59 parametric lods of 2 or greater, many of which are likely to be close to maximum possible scores. While some linkage findings may be false positives the results could help prioritize the search for rare variants using whole exome or genome sequencing.
doi:10.1038/mp.2011.89
PMCID: PMC3204161  PMID: 21769101
Bipolar disorder; Whole genome linkage; Single Nucleotide Polymorphisms; 6q21; 9q21; 2q12
10.  Genome Wide Linkage Analysis of 972 Bipolar Pedigrees Using Single Nucleotide Polymorphisms 
Molecular psychiatry  2011;17(8):818-826.
Because of the high costs associated with ascertainment of families most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. While microsatellite markers spaced every 10 centimorgans typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carry out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 SNPs. Of the ~1100 families, 972 were informative for further analyses and mean information content was 0.86 after pruning for LD. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with Bipolar II disorder (BPII) and 702 subjects with Recurrent Major Depression. Three affection status models were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus Recurrent Major Depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (Nonparametric Pairs Lod 3.4 for rs1046943 at 119 cM) and 9q21 (Nonparametric Pairs Lod 3.4 for rs722642 at 78 cM) using only BPI and SA, BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis we observed 59 parametric lods of 2 or greater, many of which are likely to be close to maximum possible scores. While some linkage findings may be false positives the results could help prioritize the search for rare variants using whole exome or genome sequencing.
doi:10.1038/mp.2011.89
PMCID: PMC3204161  PMID: 21769101
Bipolar disorder; Whole genome linkage; Single Nucleotide Polymorphisms; 6q21; 9q21; 2q12
11.  Autism: the micro-movement perspective 
The current assessment of behaviors in the inventories to diagnose autism spectrum disorders (ASD) focus on observation and discrete categorizations. Behaviors require movements, yet measurements of physical movements are seldom included. Their inclusion however, could provide an objective characterization of behavior to help unveil interactions between the peripheral and the central nervous systems (CNSs). Such interactions are critical for the development and maintenance of spontaneous autonomy, self-regulation, and voluntary control. At present, current approaches cannot deal with the heterogeneous, dynamic and stochastic nature of development. Accordingly, they leave no avenues for real time or longitudinal assessments of change in a coping system continuously adapting and developing compensatory mechanisms. We offer a new unifying statistical framework to reveal re-afferent kinesthetic features of the individual with ASD. The new methodology is based on the non-stationary stochastic patterns of minute fluctuations (micro-movements) inherent to our natural actions. Such patterns of behavioral variability provide re-entrant sensory feedback contributing to the autonomous regulation and coordination of the motor output. From an early age, this feedback supports centrally driven volitional control and fluid, flexible transitions between intentional and spontaneous behaviors. We show that in ASD there is a disruption in the maturation of this form of proprioception. Despite this disturbance, each individual has unique adaptive compensatory capabilities that we can unveil and exploit to evoke faster and more accurate decisions. Measuring the kinesthetic re-afference in tandem with stimuli variations we can detect changes in their micro-movements indicative of a more predictive and reliable kinesthetic percept. Our methods address the heterogeneity of ASD with a personalized approach grounded in the inherent sensory-motor abilities that the individual has already developed.
doi:10.3389/fnint.2013.00032
PMCID: PMC3721360  PMID: 23898241
autism spectrum disorders; stochastic kinesthetic re-afference; Gamma probability distribution; spontaneous behavioral variability; non-stationary statistics
12.  Multi-species data integration and gene ranking enrich significant results in an alcoholism genome-wide association study 
BMC Genomics  2012;13(Suppl 8):S16.
Background
A variety of species and experimental designs have been used to study genetic influences on alcohol dependence, ethanol response, and related traits. Integration of these heterogeneous data can be used to produce a ranked target gene list for additional investigation.
Results
In this study, we performed a unique multi-species evidence-based data integration using three microarray experiments in mice or humans that generated an initial alcohol dependence (AD) related genes list, human linkage and association results, and gene sets implicated in C. elegans and Drosophila. We then used permutation and false discovery rate (FDR) analyses on the genome-wide association studies (GWAS) dataset from the Collaborative Study on the Genetics of Alcoholism (COGA) to evaluate the ranking results and weighting matrices. We found one weighting score matrix could increase FDR based q-values for a list of 47 genes with a score greater than 2. Our follow up functional enrichment tests revealed these genes were primarily involved in brain responses to ethanol and neural adaptations occurring with alcoholism.
Conclusions
These results, along with our experimental validation of specific genes in mice, C. elegans and Drosophila, suggest that a cross-species evidence-based approach is useful to identify candidate genes contributing to alcoholism.
doi:10.1186/1471-2164-13-S8-S16
PMCID: PMC3535715  PMID: 23282140
13.  Individual common variants exert weak effects on the risk for autism spectrum disorderspi 
Anney, Richard | Klei, Lambertus | Pinto, Dalila | Almeida, Joana | Bacchelli, Elena | Baird, Gillian | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Casey, Jillian | Conroy, Judith | Correia, Catarina | Corsello, Christina | Crawford, Emily L. | de Jonge, Maretha | Delorme, Richard | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Folstein, Susan E. | Fombonne, Eric | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Green, Andrew | Green, Jonathan | Guter, Stephen J. | Heron, Elizabeth A. | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Jacob, Suma | Kenny, Graham P. | Kim, Cecilia | Kolevzon, Alexander | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Law-Smith, Miriam | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Liu, Xiao-Qing | Lombard, Frances | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Magalhaes, Tiago R. | Mantoulan, Carine | McDougle, Christopher J. | Melhem, Nadine M. | Merikangas, Alison | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Noakes, Carolyn | Nygren, Gudrun | Papanikolaou, Katerina | Pagnamenta, Alistair T. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Posey, David J. | Poustka, Fritz | Ragoussis, Jiannis | Regan, Regina | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Schlitt, Sabine | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stoppioni, Vera | Sykes, Nuala | Tancredi, Raffaella | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Vorstman, JAS | Wallace, Simon | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Bailey, Anthony J. | Battaglia, Agatino | Cantor, Rita M. | Coon, Hilary | Cuccaro, Michael L. | Dawson, Geraldine | Ennis, Sean | Freitag, Christine M. | Geschwind, Daniel H. | Haines, Jonathan L. | Klauck, Sabine M. | McMahon, William M. | Maestrini, Elena | Miller, Judith | Monaco, Anthony P. | Nelson, Stanley F. | Nurnberger, John I. | Oliveira, Guiomar | Parr, Jeremy R. | Pericak-Vance, Margaret A. | Piven, Joseph | Schellenberg, Gerard D. | Scherer, Stephen W. | Vicente, Astrid M. | Wassink, Thomas H. | Wijsman, Ellen M. | Betancur, Catalina | Buxbaum, Joseph D. | Cook, Edwin H. | Gallagher, Louise | Gill, Michael | Hallmayer, Joachim | Paterson, Andrew D. | Sutcliffe, James S. | Szatmari, Peter | Vieland, Veronica J. | Hakonarson, Hakon | Devlin, Bernie
Human Molecular Genetics  2012;21(21):4781-4792.
While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
doi:10.1093/hmg/dds301
PMCID: PMC3471395  PMID: 22843504
14.  A Genomewide Association Study of DSM-IV Cannabis Dependence 
Addiction biology  2010;16(3):514-518.
Despite twin studies showing that 50–70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genomewide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis dependent cases with 2,346 cannabis exposed nondependent controls was conducted using logistic regression in PLINK. None of the 948,142 SNPs met genomewide significance (p < E−8). The lowest p-values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, p-values at E−7) in the ANKFN1 gene. While replication is required, this study represents an important first step towards clarifying the biological underpinnings of cannabis dependence.
doi:10.1111/j.1369-1600.2010.00255.x
PMCID: PMC3117436  PMID: 21668797
15.  Copy Number Variation Accuracy in Genome-Wide Association Studies 
Human Heredity  2011;71(3):141-147.
Background/Aim
Copy number variations (CNVs) are a major source of alterations among individuals and are a potential risk factor in many diseases. Numerous diseases have been linked to deletions and duplications of these chromosomal segments. Data from genome-wide association studies and other microarrays may be used to identify CNVs by several different computer programs, but the reliability of the results has been questioned.
Methods
To help researchers reduce the number of false-positive CNVs that need to be followed up with laboratory testing, we evaluated the relative performance of CNVPartition, PennCNV and QuantiSNP, and developed a statistical method for estimating sensitivity and positive predictive values of CNV calls and tested it on 96 duplicate samples in our dataset.
Results
We found that the positive predictive rate increases with the number of probes in the CNV and the size of the CNV, with the highest positive predicted rates in CNVs of at least 500 kb and at least 100 probes. Our analysis also indicates that identifying CNVs reported by multiple programs can greatly improve the reproducibility rate and the positive predicted rate.
Conclusion
Our methods can be used by investigators to identify CNVs in genome-wide data with greater reliability.
doi:10.1159/000324683
PMCID: PMC3153341  PMID: 21778733
Accuracy; Copy number variations; False positives; Genome-wide association studies
16.  Cannabis involvement in individuals with Bipolar Disorder 
Psychiatry research  2010;185(3):459-461.
In a study of 471 BD cases and 1761 controls, individuals with BD were 6.8 times more likely to report a lifetime history of cannabis use. Rates of DSM-IV cannabis use disorders in those with BD were 29.4% and were independently and significantly associated with increased suicide attempts, experience mixed episodes and disability attributable to BD.
doi:10.1016/j.psychres.2010.07.007
PMCID: PMC2976789  PMID: 20674039
cannabis; bipolar disorder; comorbidity
17.  A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder 
Casey, Jillian P. | Magalhaes, Tiago | Conroy, Judith M. | Regan, Regina | Shah, Naisha | Anney, Richard | Shields, Denis C. | Abrahams, Brett S. | Almeida, Joana | Bacchelli, Elena | Bailey, Anthony J. | Baird, Gillian | Battaglia, Agatino | Berney, Tom | Bolshakova, Nadia | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Cali, Phil | Correia, Catarina | Corsello, Christina | Coutanche, Marc | Dawson, Geraldine | de Jonge, Maretha | Delorme, Richard | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Folstein, Susan E. | Foley, Suzanne | Fombonne, Eric | Freitag, Christine M. | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Green, Jonathan | Guter, Stephen J. | Hakonarson, Hakon | Holt, Richard | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Kim, Cecilia | Klauck, Sabine M. | Kolevzon, Alexander | Lamb, Janine A. | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Lord, Catherine | Lund, Sabata C. | Maestrini, Elena | Mantoulan, Carine | Marshall, Christian R. | McConachie, Helen | McDougle, Christopher J. | McGrath, Jane | McMahon, William M. | Merikangas, Alison | Miller, Judith | Minopoli, Fiorella | Mirza, Ghazala K. | Munson, Jeff | Nelson, Stanley F. | Nygren, Gudrun | Oliveira, Guiomar | Pagnamenta, Alistair T. | Papanikolaou, Katerina | Parr, Jeremy R. | Parrini, Barbara | Pickles, Andrew | Pinto, Dalila | Piven, Joseph | Posey, David J. | Poustka, Annemarie | Poustka, Fritz | Ragoussis, Jiannis | Roge, Bernadette | Rutter, Michael L. | Sequeira, Ana F. | Soorya, Latha | Sousa, Inês | Sykes, Nuala | Stoppioni, Vera | Tancredi, Raffaella | Tauber, Maïté | Thompson, Ann P. | Thomson, Susanne | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Vorstman, Jacob A. S. | Wallace, Simon | Wang, Kai | Wassink, Thomas H. | White, Kathy | Wing, Kirsty | Wittemeyer, Kerstin | Yaspan, Brian L. | Zwaigenbaum, Lonnie | Betancur, Catalina | Buxbaum, Joseph D. | Cantor, Rita M. | Cook, Edwin H. | Coon, Hilary | Cuccaro, Michael L. | Geschwind, Daniel H. | Haines, Jonathan L. | Hallmayer, Joachim | Monaco, Anthony P. | Nurnberger, John I. | Pericak-Vance, Margaret A. | Schellenberg, Gerard D. | Scherer, Stephen W. | Sutcliffe, James S. | Szatmari, Peter | Vieland, Veronica J. | Wijsman, Ellen M. | Green, Andrew | Gill, Michael | Gallagher, Louise | Vicente, Astrid | Ennis, Sean
Human Genetics  2011;131(4):565-579.
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-011-1094-6
PMCID: PMC3303079  PMID: 21996756
18.  Item response modeling of DSM-IV mania symptoms in two representative U.S. epidemiological samples 
Psychological medicine  2009;40(9):1549-1558.
Background
There is considerable debate surrounding the effective measurement of DSM-IV symptoms used to assess manic disorders in epidemiological samples.
Methods
Using two nationally representative datasets, the National Epidemiological Survey of Alcohol and Related Conditions (NESARC, N=43,093 at Wave 1, N=34,653 at 3-year follow-up) and the National Comorbidity Survey-Replication (NCS-R, N=9,282), we examined the psychometric properties of symptoms used to assess DSM-IV mania. The predictive utility of the mania factor score was tested using the 3-year follow-up data in NESARC.
Results
Criterion B symptoms were unidimensional (single factor) in both samples. The symptoms assessing flight of ideas, distractibility and increased goal-directed activities had high factor loadings (0.70–0.93) with moderate rates of endorsement thus providing good discrimination between individuals with and without mania. The symptom assessing grandiosity performed less well in both samples. The quantitative mania factor score was a good predictor of more severe disorders at 3-year follow-up in the NESARC sample, even after controlling for a past history of DSM-IV diagnosis of manic disorder.
Conclusion
These analyses suggest that questions based on some DSM symptoms effectively discriminate between individuals at high and low liability to mania, while others do not. A quantitative mania factor score may aid in predicting recurrence for patients with a history of mania. Methods for assessing mania using structured interviews in the absence of clinical assessment require further refinement.
doi:10.1017/S0033291709992005
PMCID: PMC2917338  PMID: 19951450
19.  Predicting sensation seeking from dopamine genes: A candidate system approach 
Psychological science  2010;21(9):1282-1290.
Sensation seeking is a heritable personality trait that has been reliably linked to behavior disorders. The dopamine system has been hypothesized to contribute to individual differences in sensation seeking, and both experimental and observational studies in humans and non-human animals provide evidence for this relationship. We present here a candidate-system approach to genetic association analysis of sensation seeking, in which single nucleotide polymorphisms (SNPs) from a number of dopaminergic genes were analyzed. Using 273 SNPs from eight dopamine genes in a sample of 635 unrelated individuals, we examined the aggregate effects of those SNPs significantly associated with sensation seeking. Multiple SNPs in four dopamine genes accounted for significant variance in sensation seeking. These results suggest that aggregation of multiple SNPs within genes relevant to a specific neurobiological system into a “genetic risk score” may explain a nontrivial proportion of variance in human traits.
doi:10.1177/0956797610380699
PMCID: PMC3031097  PMID: 20732903
sensation seeking; dopamine; candidate gene; association study
20.  Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes 
PLoS Genetics  2011;7(6):e1002134.
Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.
Author Summary
Bipolar disorder (BD) is a highly heritable disease that has been difficult to characterize genetically. We have genotyped 1,190 BD cases and 401 controls to find regions of the genome associated with BD. After combining these data with previously existing genotyped samples, we did not find any genome-wide significant associations. However, when we used an additional study to prioritize loci for replication and meta-analysis purposes, we found that we were more likely to see an association in our sample with variants for which we had the highest power. We quantified this effect using logistic regression and saw a strong association between power to detect an effect based on an initial study's results and replication P-value in a second study (P = 1.5×10−7), supporting the presence of shared genetic risk factors across the studies. Moreover, this association was stronger when we restricted analysis to SNPs near coding regions, and it was further enriched when SNPs had the same direction of effect in both studies. This result supports the presence of genetic factors underlying BD near exons whose collective effect results in a detectable signal and provides a framework for assessing the potential for replication when combining results from multiple studies.
doi:10.1371/journal.pgen.1002134
PMCID: PMC3128104  PMID: 21738484
21.  Genome-wide association study of alcohol dependence implicates a region on chromosome 11 
Background:
Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk.
Methods:
We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of the American Psychiatric Association Fourth Edition (DSM-IV); controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 SNPs (p ≤ 2.1 × 10−4) in a sample of alcohol dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells.
Results:
Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the followup in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2,ARL6IP5, ID4, GATA4, SYNE1 and ADCY3.
Conclusions:
We have identified several promising associations that warrant further examination in independent samples.
doi:10.1111/j.1530-0277.2010.01156.x
PMCID: PMC2884073  PMID: 20201924
alcohol dependence; genome-wide association study; case-control study; family study; gene expression
22.  Functional Impact of Global Rare Copy Number Variation in Autism Spectrum Disorder 
Pinto, Dalila | Pagnamenta, Alistair T. | Klei, Lambertus | Anney, Richard | Merico, Daniele | Regan, Regina | Conroy, Judith | Magalhaes, Tiago R. | Correia, Catarina | Abrahams, Brett S. | Almeida, Joana | Bacchelli, Elena | Bader, Gary D. | Bailey, Anthony J. | Baird, Gillian | Battaglia, Agatino | Berney, Tom | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Bryson, Susan E. | Carson, Andrew R. | Casallo, Guillermo | Casey, Jillian | Cochrane, Lynne | Corsello, Christina | Crawford, Emily L. | Crossett, Andrew | Dawson, Geraldine | de Jonge, Maretha | Delorme, Richard | Drmic, Irene | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Filipa, Ana | Folstein, Susan E. | Fombonne, Eric | Freitag, Christine M. | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Goldberg, Jeremy | Green, Andrew | Green, Jonathan | Guter, Stephen J. | Hakonarson, Hakon | Heron, Elizabeth A. | Hill, Matthew | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Kim, Cecilia | Klauck, Sabine M. | Kolevzon, Alexander | Korvatska, Olena | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Laskawiec, Magdalena | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Lionel, Anath C. | Liu, Xiao-Qing | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Maestrini, Elena | Mahoney, William | Mantoulan, Carine | Marshall, Christian R. | McConachie, Helen | McDougle, Christopher J. | McGrath, Jane | McMahon, William M. | Merikangas, Alison | Migita, Ohsuke | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Nelson, Stanley F. | Noakes, Carolyn | Noor, Abdul | Nygren, Gudrun | Oliveira, Guiomar | Papanikolaou, Katerina | Parr, Jeremy R. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Pilorge, Marion | Piven, Joseph | Ponting, Chris P. | Posey, David J. | Poustka, Annemarie | Poustka, Fritz | Prasad, Aparna | Ragoussis, Jiannis | Renshaw, Katy | Rickaby, Jessica | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Bierut, Laura J. | Rice, John P. | Consortium, SAGE | Salt, Jeff | Sansom, Katherine | Sato, Daisuke | Segurado, Ricardo | Senman, Lili | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stein, Olaf | Stoppioni, Vera | Strawbridge, Christina | Tancredi, Raffaella | Tansey, Katherine | Thiruvahindrapduram, Bhooma | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Wallace, Simon | Wang, Kai | Wang, Zhouzhi | Wassink, Thomas H. | Webber, Caleb | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Wu, Jing | Yaspan, Brian L. | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Buxbaum, Joseph D. | Cantor, Rita M. | Cook, Edwin H. | Coon, Hilary | Cuccaro, Michael L. | Devlin, Bernie | Ennis, Sean | Gallagher, Louise | Geschwind, Daniel H. | Gill, Michael | Haines, Jonathan L. | Hallmayer, Joachim | Miller, Judith | Monaco, Anthony P. | Nurnberger, John I. | Paterson, Andrew D. | Pericak-Vance, Margaret A. | Schellenberg, Gerard D. | Szatmari, Peter | Vicente, Astrid M. | Vieland, Veronica J. | Wijsman, Ellen M. | Scherer, Stephen W. | Sutcliffe, James S. | Betancur, Catalina
Nature  2010;466(7304):368-372.
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviors1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability (ID)2. While ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here, we analyzed the genome-wide characteristics of rare (<1% frequency) copy number variation (CNV) in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic CNVs (1.19 fold, P= 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P= 3.4×10−4). Among the CNVs, there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes like SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene-sets involved in cellular proliferation, projection and motility, and GTPase/Ras signaling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
doi:10.1038/nature09146
PMCID: PMC3021798  PMID: 20531469
23.  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.
doi:10.1038/nature07999
PMCID: PMC2943511  PMID: 19404256
24.  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.
doi:10.1038/nature07953
PMCID: PMC2925224  PMID: 19404257
25.  A genome-wide scan for common alleles affecting risk for autism 
Anney, Richard | Klei, Lambertus | Pinto, Dalila | Regan, Regina | Conroy, Judith | Magalhaes, Tiago R. | Correia, Catarina | Abrahams, Brett S. | Sykes, Nuala | Pagnamenta, Alistair T. | Almeida, Joana | Bacchelli, Elena | Bailey, Anthony J. | Baird, Gillian | Battaglia, Agatino | Berney, Tom | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Carson, Andrew R. | Casallo, Guillermo | Casey, Jillian | Chu, Su H. | Cochrane, Lynne | Corsello, Christina | Crawford, Emily L. | Crossett, Andrew | Dawson, Geraldine | de Jonge, Maretha | Delorme, Richard | Drmic, Irene | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Folstein, Susan E. | Fombonne, Eric | Freitag, Christine M. | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Goldberg, Jeremy | Green, Jonathan | Guter, Stephen J. | Hakonarson, Hakon | Heron, Elizabeth A. | Hill, Matthew | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Kim, Cecilia | Klauck, Sabine M. | Kolevzon, Alexander | Korvatska, Olena | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Laskawiec, Magdalena | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Lionel, Anath C. | Liu, Xiao-Qing | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Maestrini, Elena | Mahoney, William | Mantoulan, Carine | Marshall, Christian R. | McConachie, Helen | McDougle, Christopher J. | McGrath, Jane | McMahon, William M. | Melhem, Nadine M. | Merikangas, Alison | Migita, Ohsuke | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Nelson, Stanley F. | Noakes, Carolyn | Noor, Abdul | Nygren, Gudrun | Oliveira, Guiomar | Papanikolaou, Katerina | Parr, Jeremy R. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Piven, Joseph | Posey, David J | Poustka, Annemarie | Poustka, Fritz | Prasad, Aparna | Ragoussis, Jiannis | Renshaw, Katy | Rickaby, Jessica | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Bierut, Laura J. | Rice, John P. | Salt, Jeff | Sansom, Katherine | Sato, Daisuke | Segurado, Ricardo | Senman, Lili | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stoppioni, Vera | Strawbridge, Christina | Tancredi, Raffaella | Tansey, Katherine | Thiruvahindrapduram, Bhooma | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Wallace, Simon | Wang, Kai | Wang, Zhouzhi | Wassink, Thomas H. | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Yaspan, Brian L. | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Betancur, Catalina | Buxbaum, Joseph D. | Cantor, Rita M. | Cook, Edwin H. | Coon, Hilary | Cuccaro, Michael L. | Gallagher, Louise | Geschwind, Daniel H. | Gill, Michael | Haines, Jonathan L. | Miller, Judith | Monaco, Anthony P. | Nurnberger, John I. | Paterson, Andrew D. | Pericak-Vance, Margaret A. | Schellenberg, Gerard D. | Scherer, Stephen W. | Sutcliffe, James S. | Szatmari, Peter | Vicente, Astrid M. | Vieland, Veronica J. | Wijsman, Ellen M. | Devlin, Bernie | Ennis, Sean | Hallmayer, Joachim
Human Molecular Genetics  2010;19(20):4072-4082.
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
doi:10.1093/hmg/ddq307
PMCID: PMC2947401  PMID: 20663923

Results 1-25 (36)