Susan E. Folstein’s research while affiliated with University of Miami and other places

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Publications (172)


Fig. 2 Association locus plot for the index SNP rs1409313 in the GWAS of all (worldwide) ancestries autism spectrum disorder. The GWS association (pink diamond) refers to the combined PGC-iPSYCH meta-analyses. Additional panels include gene location and location of eQTL markers 
Table 3 Novel GWS loci from combined ASD-schizophrenia GWAS 
Sign test of concordance of the direction of effect (odds ratio) of the discovery (PGC worldwide) and the replication sample (a replication set 1: iPSYCH; b replication set 2: deCODE/SEED). Blue line is the –log10(P) of the binomial sign test for all associated markers below the rank. The green line describes the concordance, and the grey markers the association in the discovery set
Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
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May 2017

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1,075 Reads

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469 Citations

Molecular Autism

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Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.

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Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

April 2014

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922 Reads

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910 Citations

The American Journal of Human Genetics

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.



Commentary on Kerns and Kendall

December 2012

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43 Reads

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6 Citations

The field has been uncertain about how to think about anxiety as it occurs in persons with autism spectrum disorder (ASD). Kerns and Kendall (2012) review the relevant empirical literature and conclude that the preponderance of evidence suggests that anxiety is a co-occurring condition with ASD. I agree with this conclusion. However, my agreement is not based on the literature but rather because when anxiety can be identified and treated with anxiolytics in a person with autism, the person's functioning is improved. As the authors point out, identification of anxiety is not always easy, and improved methods of detection are needed.


Table 1 . The sample size for specific family-based analyses
Table 2 . Top hits from the primary analyses in the combined AGP GWA sample
Table 3 . The most associated SNPs from the secondary analyses in the combined sample
Table 4 . Top hits from regions previously implicated as autism susceptibility regions from non-AGP studies
Additive genetic variance at marker (VM) explained by the Stage 1-derived allele score in Stage 2 probands and pseudo controls for a given ancestry and diagnostic classification. Significant association of the allele score denoted by (*P< 0.05, **P< 0.01, ***P< 0.001). Note that the number of predictors, at a given threshold, is roughly the threshold times the number of SNPs meeting quality control criteria (947 233).
Individual common variants exert weak effects on the risk for autism spectrum disorders

July 2012

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355 Reads

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386 Citations

Human Molecular Genetics

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.



A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

October 2011

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397 Reads

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193 Citations

Human Genetics

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.





Citations (88)


... The difference in results can be explained in various ways. First, ASD is by nature heterogeneous and symptoms vary according to the level of ASD (Santangelo and Folstein, 1999;Tager-Flusberg and Joseph, 2003); in our study, all participants with ASD were level 1. Second, within ASD there can be subgroups defined by performance in terms of central coherence (Tager-Flusberg and Joseph, 2003). ...

Reference:

Weak central coherence in neurodevelopmental disorders: a comparative study
Autism: A Genetic Perspective
  • Citing Chapter
  • June 1999

... Other intronic variants in MACROD2 have been associated with the ceramides and sphingomyelins, suggesting a potential role in lipids pathways [44]. There is a large body of evidence for associations of intronic variants in MACROD2 with complex psychosocial, neurological, and psychiatric traits, including: attention deficit hyperactivity disorder [45,46], morningness (being a morning person) [47], risk-taking behavior [48], eating disorders [49], autism [50][51][52], and bipolar disorder [52,53]. Infants with atypical neonatal neurobehavioral scores had differentially methylated CpG sites within the MACROD2 gene [54]. ...

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Molecular Autism

... Recent studies have suggested that autism and specific language impairment may have overlapping genetic aetiologies (19)(20)(21). Therefore, we tested the hypothesis that the linkage on chromosome 7q could be attributed to a gene responsible for language development. ...

Evidence for variation ln the language phenotype for autism: Implications for genetic subgroups.
  • Citing Article
  • September 1999

Molecular Psychiatry

... Additional tools that have been used in investigations of the BAP include the Children's Communication Checklist-2 (Bishop, 2003), the Pragmatic Rating Scale (Landa et al., 1992), and the Friendship Interview (Santangelo & Folstein, 1995). Unlike the surveys described above, these tools are more focused on the domains that they address. ...

Social deficits in the families of autistic probands
  • Citing Article
  • October 1995

The American Journal of Human Genetics

... ASD consists of a set of developmental disabilities that impacts socialcommunication and behavior (American Psychiatric Association, 2013). These behaviors include deficits in social interactions, lack of interest in playing with other children, and abnormal use of language (Folstein, 1999;Shire et al., 2015;Wetherby, Watt, Morgan, & Shumway, 2007). According to Gibson, Adams, Lockton, and Green (2013) and Kuder (2012), communication is an important factor in children with ASD and many of them do not develop spoken language. ...

Autism
  • Citing Article
  • November 1999

... In addition to individual loci, significant CNV enrichments in specific gene networks have been associated with NDDs. In this regard, our group and others have identified significant CNV enrichment within the in metabotropic glutamatergic receptor (mGluR) network among independent ASD and ADHD cohorts [10][11][12][13][14][15]. These data suggest that mGluR network genes may serve as hubs that coordinate highly connected modules of interacting genes, many of which may harbor CNVs and are enriched for synaptic and neuronal biological functions. ...

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

... Após isso, foi aplicado o Mini Exame do estado mental (MEEM) (Folstein, Folstein, & McHugh, 2007). Este foi aplicado apenas para identificar se o sujeito estava apto para participar da pesquisa conforme critérios de inclusão. ...

Mini Mental State Examination (MMSE) - probably one of the most cited papers in health science - Reply
  • Citing Article
  • August 2007

Acta Psychiatrica Scandinavica

... Some of the factors associated with diminished environmental input also occur within the familial autism context and thus may influence the dyadic interactions and early language development of infant siblings. These include mothers' broader autism phenotype characteristics and depressive symptoms, both of which are elevated in parents of children with ASD and are associated with differences in pragmatic language use and reduced linguistic input, respectively (Bailey, Golden, Roberts, & Ford, 2007;Ingersoll & Hambrick, 2011;Lindgren, Folstein, Tomblin, & Tager-Flusberg, 2010;Ruser et al., 2007). The elevated levels of concern consistently reported by mothers of high risk infants across the first year of life may also be associated with reduced linguistic input to the extent that those concerns reflect increased anxiety and a less sensitive pattern of responding (Hess & Landa, 2012;Ozonoff et al., 2009;Sacrey et al., 2015;Talbott, Nelson, & Tager-Flusberg, 2015a). ...

Language and Reading Abilities of Children with Autism and SLI and Their First-Degree Relatives
  • Citing Conference Paper
  • May 2008

... DSM and distinct anxiety were not significantly associated in children with ASD and intellectual impairment, but this may be explained by the limited amount and variety of DSM anxiety in this group. Moreover, the base rates of significant distinct anxiet (6-23%) were not consistent with their being conceptualized as integral or inevitable consequences of ASD (Folstein, 2012). Kerns et al. (2014) also reported that significant DSM and distinct anxiety occur in a substantial subset, but not all, children with ASD and were more strongly related to one another than ASD severity. ...

Commentary on Kerns and Kendall

... Large-scale genetic studies show significant overlap in risk genes for ASD, SCZ, and BPD, many converging on synaptic proteins (Carroll and Owen, 2009;Purcell et al., 2014;Satterstrom et al., 2020;Genovese et al., 2016;Fromer et al., 2014;De Rubeis et al., 2014;Iossifov et al., 2014;Pinto et al., 2014;Kirov et al., 2012). However, how variants in a single gene contribute to different NDDs remains a major unresolved question. ...

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

The American Journal of Human Genetics