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Mark S Silverberg,
Judy H Cho,
John D Rioux,
Dermot P B McGovern,
Jing Wu,
Vito Annese,
Jean-Paul Achkar,
Philippe Goyette,
Regan Scott,
Wei Xu, [......],
Stephan R Targan,
L Philip Schumm,
Emily O Kistner,
Annette T Lee,
Peter K Gregersen,
Jerome I Rotter,
Steven R Brant,
Kent D Taylor,
Kathryn Roeder,
Richard H Duerr
Nature Genetics 07/2009; 41(6):762. · 35.53 Impact Factor
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Laura M Yerges, Lambertus Klei,
Jane A Cauley,
Kathryn Roeder,
Candace M Kammerer,
Susan P Moffett,
Kristine E Ensrud,
Cara S Nestlerode,
Lynn M Marshall,
Andrew R Hoffman,
Cora Lewis,
Thomas F Lang,
Elizabeth Barrett-Connor,
Robert E Ferrell,
Eric S Orwoll,
Joseph M Zmuda
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ABSTRACT: Genetics is a well-established but poorly understood determinant of BMD. Whereas some genetic variants may influence BMD throughout the body, others may be skeletal site specific. We initially screened for associations between 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes and femoral neck and lumbar spine volumetric BMD (vBMD) measured from QCT scans among 862 community-dwelling white men >or=65 yr of age in the Osteoporotic Fractures in Men Study (MrOS). The most promising SNP associations (p < 0.01) were validated by genotyping an additional 1156 white men from MrOS. This analysis identified 8 SNPs in 6 genes (APC, DMP1, FGFR2, FLT1, HOXA, and PTN) that were associated with femoral neck vBMD and 13 SNPs in 7 genes (APC, BMPR1B, FOXC2, HOXA, IGFBP2, NFATC1, and SOST) that were associated with lumbar spine vBMD in both genotyping samples (p < 0.05). Although most associations were specific to one skeletal site, SNPs in the APC and HOXA gene regions were associated with both femoral neck and lumbar spine BMD. This analysis identifies several novel and robust genetic associations for volumetric BMD, and these findings in combination with other data suggest the presence of genetic loci for volumetric BMD that are at least to some extent skeletal-site specific.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2009; 24(12):2039-49. · 6.04 Impact Factor
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ABSTRACT: As one approach to uncovering the genetic underpinnings of complex disease, individuals are measured at a large number of genetic variants (usually SNPs) across the genome and these SNP genotypes are assessed for association with disease status. We propose a new statistical method called Spectral-GEM for the analysis of genome-wide association studies; the goal of Spectral-GEM is to quantify the ancestry of the sample from such genotypic data. Ignoring structure due to differential ancestry can lead to an excess of spurious findings and reduce power. Ancestry is commonly estimated using the eigenvectors derived from principal component analysis (PCA). To develop an alternative to PCA we draw on connections between multidimensional scaling and spectral graph theory. Our approach, based on a spectral embedding derived from the normalized Laplacian of a graph, can produce more meaningful delineation of ancestry than by using PCA. Often the results from Spectral-GEM are straightforward to interpret and therefore useful in association analysis. We illustrate the new algorithm with an analysis of the POPRES data [Nelson et al., 2008].
Genetic Epidemiology 06/2009; 34(1):51-9. · 3.44 Impact Factor
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Joseph T Glessner,
Kai Wang,
Guiqing Cai,
Olena Korvatska,
Cecilia E Kim,
Shawn Wood,
Haitao Zhang,
Annette Estes,
Camille W Brune,
Jonathan P Bradfield, [......],
Hilary Coon,
James S Sutcliffe,
Nancy J Minshew,
Struan F A Grant,
Maja Bucan,
Edwin H Cook,
Joseph D Buxbaum,
Bernie Devlin,
Gerard D Schellenberg,
Hakon Hakonarson
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ABSTRACT: Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. 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 approximately 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 x 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 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 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.
Nature 05/2009; 459(7246):569-73. · 36.28 Impact Factor
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Joseph T. Glessner,
Kai Wang,
Guiqing Cai,
Olena Korvatska,
Cecilia E. Kim,
Shawn Wood,
Haitao Zhang,
Annette Estes,
Camille W. Brune,
Jonathan P. Bradfield, [......],
Hilary Coon,
James S. Sutcliffe,
Nancy J. Minshew,
Struan F. A. Grant,
Maja Bucan,
Edwin H. Cook,
Joseph D. Buxbaum,
Bernie Devlin,
Gerard D. Schellenberg,
Hakon Hakonarson
Nature 04/2009; 459(7246):569-573. · 36.28 Impact Factor
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Hader Mansour, Lambertus Klei,
Joel Wood,
Michael Talkowski,
Kodavali Chowdari,
Warda Fathi,
Ahmed Eissa,
Amal Yassin,
Hala Salah,
Salwa Tobar, [......],
Mai Elassy,
Nahed E Ibrahim,
Wafaa El-Bahaei,
Mohamed Elsayed,
Mohamed Shahda,
Eman El Sheshtawy,
Osama El-Boraie,
Farha El-Chennawi,
Bernie Devlin,
Vishwajit L Nimgaonkar
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ABSTRACT: We aimed to contrast rates of consanguinity among patients with bipolar I disorder (BP1) and controls in a population with customary consanguineous marriages (i.e., marriage between related individuals). Consanguinity increases risk for numerous monogenic and polygenic diseases. Whether the risk for BP1 increases with consanguinity has not been investigated systematically. Two independent studies were conducted in Egypt: (1) Case-control study 93 patients with BP1, 90 screened adult control individuals, and available parents. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms ("DNA-based" rate); and from family history data ("self report"); (2) Epidemiological survey: total of 1,584 individuals were screened, from whom self-reported consanguinity data were obtained for identified BP1 cases (n = 35) and 150 randomly selected, unaffected control individuals. DNA-based consanguinity rates showed significant case-control differences (P = 0.0039). Self-reported consanguinity rates were also elevated among BP1 patients in both samples (Study #1 OR = 2.66, 95% confidence intervals, CI: 1.34, 5.29; Study #2: OR = 4.64, 95% CI: 2.01, 10.34). In conclusion, two independent, systematic studies indicate increased consanguinity among Egyptian BP1 patients in the Nile delta region. Self-reported estimates of consanguinity are bolstered by DNA-based estimates, and both show significant case-control differences for BP1.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2009; 150B(6):879-85. · 3.70 Impact Factor
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Mark S Silverberg,
Judy H Cho,
John D Rioux,
Dermot P B McGovern,
Jing Wu,
Vito Annese,
Jean-Paul Achkar,
Philippe Goyette,
Regan Scott,
Wei Xu, [......],
Stephan R Targan,
L Philip Schumm,
Emily O Kistner,
Annette T Lee,
Peter K Gregersen,
Jerome I Rotter,
Steven R Brant,
Kent D Taylor,
Kathryn Roeder,
Richard H Duerr
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ABSTRACT: Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).
Nature Genetics 02/2009; 41(2):216-20. · 35.53 Impact Factor
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Diana Luca,
Steven Ringquist, Lambertus Klei,
Ann B Lee,
Christian Gieger,
H-Erich Wichmann,
Stefan Schreiber,
Michael Krawczak,
Ying Lu,
Alexis Styche,
Bernie Devlin,
Kathryn Roeder,
Massimo Trucco
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ABSTRACT: Resources being amassed for genome-wide association (GWA) studies include "control databases" genotyped with a large-scale SNP array. How to use these databases effectively is an open question. We develop a method to match, by genetic ancestry, controls to affected individuals (cases). The impact of this method, especially for heterogeneous human populations, is to reduce the false-positive rate, inflate other spuriously small p values, and have little impact on the p values associated with true positive loci. Thus, it highlights true positives by downplaying false positives. We perform a GWA by matching Americans with type 1 diabetes (T1D) to controls from Germany. Despite the complex study design, these analyses identify numerous loci known to confer risk for T1D.
The American Journal of Human Genetics 03/2008; 82(2):453-63. · 10.60 Impact Factor
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ABSTRACT: When many correlated traits are measured the potential exists to discover the coordinated control of these traits via genotyped polymorphisms. A common statistical approach to this problem involves assessing the relationship between each phenotype and each single nucleotide polymorphism (SNP) individually (PHN); and taking a Bonferroni correction for the effective number of independent tests conducted. Alternatively, one can apply a dimension reduction technique, such as estimation of principal components, and test for an association with the principal components of the phenotypes (PCP) rather than the individual phenotypes. Building on the work of Lange and colleagues we develop an alternative method based on the principal component of heritability (PCH). For each SNP the PCH approach reduces the phenotypes to a single trait that has a higher heritability than any other linear combination of the phenotypes. As a result, the association between a SNP and derived trait is often easier to detect than an association with any of the individual phenotypes or the PCP. When applied to unrelated subjects, PCH has a drawback. For each SNP it is necessary to estimate the vector of loadings that maximize the heritability over all phenotypes. We develop a method of iterated sample splitting that uses one portion of the data for training and the remainder for testing. This cross-validation approach maintains the type I error control and yet utilizes the data efficiently, resulting in a powerful test for association.
Genetic Epidemiology 02/2008; 32(1):9-19. · 3.44 Impact Factor
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ABSTRACT: While liability to schizophrenia (Scz) is due to genetic and environmental factors, specific factors are largely unknown. We postulate a two-hit model for Scz, in which initial liability is generated during fetal brain development: this "hit" is precipitated by environmental stressors biologically interacting with maternal genetic vulnerability to the stress. Additional liability to Scz is generated by individual genetic vulnerability. To evaluate these putative levels of vulnerability, we search in the genome of both affected individuals and their mothers for variation that differs, statistically, from that in the general population. For parental analyses, mothers were treated as "affected," rather than their offspring, and the fathers were treated as "controls". We used a sample from the Palauan population: 175 individuals diagnosed with Scz, broadly defined; 87 mothers and 45 fathers of affected individuals. Pedigree and diagnostic data were available on 2,953 living and deceased subjects. DNA from 553 individuals was genotyped for short tandem repeats (STR) spaced approximately every 10 cM across the genome. We tested for association between affection status and STR alleles; such an approach was reasonable, despite the widely spaced markers, because this population has far-ranging linkage disequilibrium (LD). Results for the truly affected individuals were modest, whereas results from the maternal generation were promising. For a recessive model and a test for excess allele matching across mothers, significant findings occurred for D20S481, D10S1221, D6S1021, D13S317, and D18S976. Regions in which at least two adjacent markers produced substantial association statistics include 2p12-11.2, 2q24.1-32.1, 6q12-14.1, 10q23.2-24.21, 12q23.2-24.21 and 17q23.2-23.3.
Human Genetics 08/2007; 121(6):675-84. · 5.07 Impact Factor
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ABSTRACT: Samples consisting of a mix of unrelated cases and controls, small pedigrees, and much larger pedigrees present a unique challenge for association studies. Few methods are available for efficient analysis of such a broad spectrum of data structures. In this paper we introduce a new matching statistic that is well suited to complex data structures and compare it with frequency-based methods available in the literature. To investigate and compare the power of these methods we simulate datasets based on complex pedigrees. We examine the influence of various levels of linkage disequilibrium (LD) of the disease allele with a marker allele (or equivalently a haplotype). For low frequency marker alleles/haplotypes, frequency-based statistics are more powerful in detecting association. In contrast, for high frequency marker alleles, the matching statistic has greater power. The highest power for frequency-based statistics occurs when the disease allele frequency closely matches the frequency of the linked marker allele. In contrast maximum power of the matching statistic always occurs for intermediate marker allele frequency regardless of the disease allele frequency. Moreover, the matching and frequency-based statistics exhibit little correlation. We conclude that these two approaches can be viewed as complementary in finding possible association between a disease and a marker for many different situations.
Human Genetics 07/2007; 121(5):549-57. · 5.07 Impact Factor
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Peter Szatmari,
Andrew D Paterson,
Lonnie Zwaigenbaum,
Wendy Roberts,
Jessica Brian,
Xiao-Qing Liu,
John B Vincent,
Jennifer L Skaug,
Ann P Thompson,
Lili Senman, [......],
Jeff Salt,
Catherine Lord,
Christina Corsello,
Vanessa Hus,
Daniel E Weeks,
Fred Volkmar,
Maïté Tauber,
Eric Fombonne,
Andy Shih,
Kacie J Meyer
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ABSTRACT: Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
Nature Genetics 04/2007; 39(3):319-28. · 35.53 Impact Factor
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ABSTRACT: We report on linkage analysis of a completely ascertained population of familial psychosis derived from the oceanic nation of Palau. Palau, an archipelago of islands in the Southern Pacific, currently has a population of approximately 23,000 individuals. The peoples of Palau populated these islands recently in human history, approximately 2,000 years ago. As both historical and genetic evidence suggest, the population is far more homogeneous than most other populations undergoing genetic studies, and should therefore prove quite useful for mapping genetic variants having a meaningful impact on susceptibility to psychotic disorders. Moreover, for our study, essentially all on-island schizophrenics (150) and individuals with other psychotic disorders (25) participated. By analysis of narrow (only schizophrenia) and broad (all psychosis) diagnostic schemes, two-point linkage analyses suggest that two regions of the genome harbor genetic variants affecting liability in most families, 3q28 (LOD = 3.03) and 17q32.2 (LOD = 2.80). Results from individual pedigrees also support 2q37.2, 2p14, and 17p13 as potentially harboring important genetic variants. Most of these regions have been implicated in other genetic studies of psychosis in populations physically quite distant from this Oceanic population, although some (e.g., 3q28) appear to be novel results for schizophrenia linkage analyses.
Human Genetics 09/2005; 117(4):349-56. · 5.07 Impact Factor
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ABSTRACT: Individual variation in the phase and amplitude of human circadian rhythms is well known, but the impact of heritable factors on such variation is less clear. We estimated the narrow-sense heritability for selected circadian and sleep timing, quality, and duration measures among related members of the Hutterites, an endogamous, religious community (n=521 participants). "Morningness-eveningness" (M/E), a stable trait reflecting circadian phase, was evaluated using the Composite Scale (CS). Subjective sleep measures were assessed using the Sleep Timing Questionnaire. Initial analyses reconfirmed the impact of age on M/E. Previously reported correlations between M/E scores and the sleep measures were also noted, demonstrating the construct validity of the questionnaires among the participants. Following corrections for age, gender, and colony of residence, significant narrow-sense heritability was noted for M/E (23%). The heritability for subjective sleep measures (related to timing, duration, and quality) were statistically significant for all but one variable, and varied between 12.4% and 29.4%. Thus, significant heritable influences on human circadian phase and subjective sleep indices can be detected through family-based studies. In view of the impact of circadian malfunction on human health, it may be worthwhile to map genetic factors impacting circadian and sleep variation.
Chronobiology International 02/2005; 22(6):1041-54. · 4.03 Impact Factor
