Publications by authors named "Jesen A Fagerness"

11 Publications

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Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

Am J Psychiatry 2015 Jan 31;172(1):82-93. Epub 2014 Oct 31.

From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; the Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; the Department of Psychiatry, University of California, San Francisco; the Department of Neurology, Massachusetts General Hospital, Boston; the Division of Cognitive and Behavioral Neurology, Brigham and Women's Hospital, Boston; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles; the Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Md.; the Genomic and Bioinformatic Unit, Filarete Foundation, Milan, Italy; the Department of Health Sciences, Graduate School of Nephrology, University of Milan, Milan; the Toronto Western Research Institute, University Health Network, Toronto; Hospital for Sick Children, Toronto; Università Vita-Salute San Raffaele, Milan; the Herman Dana Division of Child and Adolescent Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem; Universidad de Antioquia, Universidad Pontificia Bolivariana, Medellín, Colombia; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; the Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; North Shore-Long Island Jewish Medical Center and North Shore-Lo

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.

Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.

Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).

Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
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http://dx.doi.org/10.1176/appi.ajp.2014.13101306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282594PMC
January 2015

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.

J Am Acad Child Adolesc Psychiatry 2014 Aug 24;53(8):910-9. Epub 2014 Jun 24.

Yale University School of Medicine, New Haven, CT.

Objective: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.

Method: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.

Results: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).

Conclusion: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.
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http://dx.doi.org/10.1016/j.jaac.2014.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218748PMC
August 2014

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

Proc Natl Acad Sci U S A 2010 Apr 12;107(16):7401-6. Epub 2010 Apr 12.

Center for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.
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http://dx.doi.org/10.1073/pnas.0912702107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867722PMC
April 2010

Genetic profile for five common variants associated with age-related macular degeneration in densely affected families: a novel analytic approach.

Eur J Hum Genet 2010 Apr 21;18(4):496-501. Epub 2009 Oct 21.

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.

About 40% of the genetic variance of age-related macular degeneration (AMD) can be explained by a common variation at five common single-nucleotide polymorphisms (SNPs). We evaluated the degree to which these known variants explain the clustering of AMD in a group of densely affected families. We sought to determine whether the actual number of risk alleles at the five variants in densely affected families matched the expected number. Using data from 322 families with AMD, we used a simulation strategy to generate comparison groups of families and determined whether their genetic profile at the known AMD risk loci differed from the observed genetic profile, given the density of disease observed. Overall, the genotypic loads for the five SNPs in the families did not deviate significantly from the genotypic loads predicted by the simulation. However, for a subset of densely affected families, the mean genotypic load in the families was significantly lower than the expected load determined from the simulation. Given that these densely affected families may harbor rare, more penetrant variants for AMD, linkage analyses and resequencing targeting these families may be an effective approach to finding additional implicated genes.
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http://dx.doi.org/10.1038/ejhg.2009.185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911949PMC
April 2010

Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables.

Invest Ophthalmol Vis Sci 2009 May 30;50(5):2044-53. Epub 2008 Dec 30.

Ophthalmic Epidemiology and Genetics Service, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts 02111, USA.

Purpose: The joint effects of genetic, ocular, and environmental variables were evaluated and predictive models for prevalence and incidence of AMD were assessed.

Methods: Participants in the multicenter Age-Related Eye Disease Study (AREDS) were included in a prospective evaluation of 1446 individuals, of which 279 progressed to advanced AMD (geographic atrophy or neovascular disease) and 1167 did not progress during 6.3 years of follow-up. For prevalent AMD, 509 advanced cases were compared with 222 controls. Covariates for the incidence analysis included age, sex, education, smoking, body mass index (BMI), baseline AMD grade, and the AREDS vitamin-mineral treatment assignment. DNA specimens were evaluated for six variants in five genes related to AMD. Unconditional logistic regression analyses were performed for prevalent and incident advanced AMD. An algorithm was developed and receiver operating characteristic curves and C statistics were calculated to assess the predictive ability of risk scores to discriminate progressors from nonprogressors.

Results: All genetic polymorphisms were independently related to prevalence of advanced AMD, controlling for genetic factors, smoking, BMI, and AREDS treatment. Multivariate odds ratios (ORs) were 3.5 (95% confidence interval [CI], 1.7-7.1) for CFH Y402H; 3.7 (95% CI, 1.6-8.4) for CFH rs1410996; 25.4 (95% CI, 8.6-75.1) for LOC387715 A69S (ARMS2); 0.3 (95% CI, 0.1-0.7) for C2 E318D; 0.3 (95% CI, 0.1-0.5) for CFB; and 3.6 (95% CI, 1.4-9.4) for C3 R102G, comparing the homozygous risk/protective genotypes to the referent genotypes. For incident AMD, all these variants except CFB were significantly related to progression to advanced AMD, after controlling for baseline AMD grade and other factors, with ORs from 1.8 to 4.0 for presence of two risk alleles and 0.4 for the protective allele. An interaction was seen between CFH402H and treatment, after controlling for all genotypes. Smoking was independently related to AMD, with a multiplicative joint effect with genotype on AMD risk. The C statistic for the full model with all variables was 0.831 for progression to advanced AMD.

Conclusions: Factors reflective of nature and nurture are independently related to prevalence and incidence of advanced AMD, with excellent predictive power.
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http://dx.doi.org/10.1167/iovs.08-3064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772781PMC
May 2009

Variation near complement factor I is associated with risk of advanced AMD.

Eur J Hum Genet 2009 Jan 6;17(1):100-4. Epub 2008 Aug 6.

Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.

A case-control association study for advanced age-related macular degeneration was conducted to explore several regions of interest identified by linkage. This analysis identified a single nucleotide polymorphism just 3' of complement factor I on chromosome 4 showing significant association (P<10(-7)). Sequencing was performed on coding exons in linkage disequilibrium with the detected association. No obvious functional variation was discovered that could be the proximate cause of the association, suggesting a noncoding regulatory mechanism.
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http://dx.doi.org/10.1038/ejhg.2008.140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2985963PMC
January 2009

Association of SNPs and haplotypes in APOL1, 2 and 4 with schizophrenia.

Schizophr Res 2008 Sep 16;104(1-3):153-64. Epub 2008 Jul 16.

Division of Psychiatry, Department of Psychiatry, Nihon University, School of Medicine, Tokyo, Japan.

Prior work found the APOL1, 2 and 4 genes, located on chromosome 22q12.3-q13.1, to be upregulated in brains of schizophrenic patients. We performed a family-based association study using 130 SNPs tagging the APOL gene family (APOL1-6). The subjects were 112 African-American (AA), 114 European-American (EA), 109 Chinese (Ch) and 42 Japanese (Jp) families with schizophrenia (377 families, 1161 genotyped members and 647 genotyped affected in total). Seven SNPs had p-values<0.05 in the APOL1, 2 and 4 regions for the AA, EA and combined (AA and EA) samples. In the AA sample, two SNPs, rs9610449 and rs6000200 showed low p-values; and a haplotype which comprised these two SNPs yielded a p-value of 0.00029 using the global test (GT) and the allele specific test (AST). The two SNPs and the haplotype were associated with risk for schizophrenia in African-Americans. In the combined (AA and EA) sample, two SNPs, rs2003813 and rs2157249 showed low p-values; and a three SNP haplotype including these two SNPs was significant using the GT (p=0.0013) and the AST (p=0.000090). The association of this haplotype with schizophrenia was significant for the entire (AA, EA, Ch and Jp) sample using the GT (p=0.00054) and the AST (p=0.00011). Although our study is not definitive, it suggests that the APOL genes should be more extensively studied in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2008.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736834PMC
September 2008

Influence of RGS2 on anxiety-related temperament, personality, and brain function.

Arch Gen Psychiatry 2008 Mar;65(3):298-308

Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Context: Although anxiety disorders are heritable, their genetic and phenotypic complexity has made the identification of susceptibility genes difficult. Well-validated animal models and intermediate phenotypes provide crucial tools for genetic dissection of anxiety. The gene encoding regulator of G protein signaling 2 (Rgs2) is a quantitative trait gene that influences mouse anxiety behavior, making its human ortholog (RGS2) a compelling candidate gene for human anxiety phenotypes.

Objective: To examine whether variation in RGS2 is associated with intermediate phenotypes for human anxiety disorders.

Design: Family-based and case-control association analysis of single-nucleotide polymorphisms at the RGS2 locus in 3 independent samples.

Setting: Massachusetts General Hospital, University of California, San Diego, and San Diego State University.

Participants: Study participants included a family-based sample (n = 119 families) of children who underwent laboratory-based assessments of temperament (behavioral inhibition), a sample of 744 unrelated adults who completed assessments of extraversion and introversion, and 55 unrelated adults who underwent functional magnetic resonance imaging measures of response to emotional faces.

Main Outcome Measures: Laboratory-based behavioral measures of childhood temperament, self-report measure of personality, and functional magnetic resonance imaging response to emotion processing.

Results: Markers spanning RGS2 were associated with childhood behavioral inhibition, a temperamental precursor of social anxiety disorder (haplotype P = 3 x 10(-5); odds ratio, 2.99 in complete trios). In independent samples, RGS2 markers, including rs4606, which has previously been associated with RGS2 expression, were also associated with introversion (a core personality trait in social anxiety disorder) and with increased limbic activation (insular cortex and amygdala) during emotion processing (brain phenotypes correlated with social anxiety). The genotype at rs4606 explained 10% to 15% of the variance in amygdala and insular cortex activation to emotional faces.

Conclusions: These results provide the first evidence that a gene that influences anxiety in mice is associated with intermediate phenotypes for human anxiety disorders across multiple levels of assessment, including childhood temperament, adult personality, and brain function. This translational research suggests that some genetic influences on anxiety are evolutionarily conserved and that pharmacologic modulation of RGS2 function may provide a novel therapeutic approach for anxiety disorders.
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http://dx.doi.org/10.1001/archgenpsychiatry.2007.48DOI Listing
March 2008

Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder.

Am J Med Genet B Neuropsychiatr Genet 2007 Dec;144B(8):1027-33

Psychiatric Neurodevelopmental and Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

Context: Obsessive-Compulsive Disorder (OCD) is a debilitating illness with putative glutamatergic abnormalities. Two separate proximal haplotypes in the glutamate transporter gene, SLC1A1, were recently reported to be associated with OCD among males, but replication is required.

Objectives: This study examines SLC1A1 as a candidate gene for OCD and explores gender influences. It was hypothesized that a significant association between SLC1A1 and OCD would be replicated in an independent sample of males but not females.

Design: Family-based association candidate gene study.

Setting: Participants were recruited from tertiary care OCD specialty clinics.

Participants: OCD probands and their first degree relatives.

Main Outcomes Measures: Association of OCD with genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes.

Results: Association between OCD and the three-marker haplotype rs12682807/ rs2072657/ rs301430, with overtransmission of A/T/T, was observed in both genders combined (global P = 0.0015) and in males (global P = 0.0031). Single-marker associations with OCD in the region (rs3780412 and rs2228622) demonstrated modest significance (permuted P = 0.045).

Conclusions: This study identifies a significant association between the SLC1A1 glutamate transporter gene and OCD in a haplotype overlapping with that recently reported.
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http://dx.doi.org/10.1002/ajmg.b.30533DOI Listing
December 2007

Variation in complement factor 3 is associated with risk of age-related macular degeneration.

Nat Genet 2007 Oct 2;39(10):1200-1. Epub 2007 Sep 2.

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

The association of variants in complement factors H and B with age-related macular degeneration has led to more intense genetic and functional analysis of the complement pathway. We identify a nonsynonymous coding change in complement factor 3 that is strongly associated with risk of age-related macular degeneration in a large case-control sample.
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http://dx.doi.org/10.1038/ng2131DOI Listing
October 2007

The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder.

Biol Psychiatry 2005 Jun;57(12):1485-92

Department of Psychiatry, Massachusetts General Hospital, Boston 02114, USA.

Background: Behavioral inhibition to the unfamiliar (BI) is a heritable temperamental phenotype involving the tendency to display fearful, avoidant, or shy behavior in novel situations. BI is a familial and developmental risk factor for panic and phobic anxiety disorders. We previously observed an association between BI and a microsatellite marker linked to the corticotropin releasing hormone (CRH) gene in children at risk for panic disorder. To evaluate this further, we genotyped additional families for this marker and a panel of markers encompassing the CRH locus.

Methods: Sixty-two families that included parents with panic disorder and children who underwent laboratory-based behavioral observations were studied. Family-based association tests and haplotype analysis were used to evaluate the association between BI and polymorphisms spanning the CRH locus.

Results: We examined a set of markers which we found to reside in a block of strong linkage disequilibrium encompassing the CRH locus. The BI phenotype was associated with the microsatellite marker (p=.0016) and three single nucleotide polymorphisms (SNPs), including a SNP in the coding sequence of the gene (p=.023). Haplotype-specific tests revealed association with a haplotype comprising all of the markers (p=.015).

Conclusions: These results suggest that the CRH gene influences inhibited temperament, a risk factor for panic and phobic anxiety disorders. Genetic studies of anxiety-related temperament represent an important strategy for identifying the genetic basis of anxiety disorders.
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http://dx.doi.org/10.1016/j.biopsych.2005.02.018DOI Listing
June 2005