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Affected Sibling Pairs (affected + sibling_pair)
Selected AbstractsUsing sex-averaged genetic maps in multipoint linkage analysis when identity-by-descent status is incompletely knownGENETIC EPIDEMIOLOGY, Issue 5 2006Tasha E. Fingerlin Abstract The ratio of male and female genetic map distances varies dramatically across the human genome. Despite these sex differences in genetic map distances, most multipoint linkage analyses use sex-averaged genetic maps. We investigated the impact of using a sex-averaged genetic map instead of sex-specific maps for multipoint linkage analysis of affected sibling pairs when identity-by-descent states are incompletely known due to missing parental genotypes and incomplete marker heterozygosity. If either all or no parental genotypes were available, for intermarker distances of 10, 5, and 1,cM, we found no important differences in the expected maximum lod score (EMLOD) or location estimates of the disease locus between analyses that used the sex-averaged map and those that used the true sex-specific maps for female:male genetic map distance ratios 1:10 and 10:1. However, when genotypes for only one parent were available and the recombination rate was higher in females, the EMLOD using the sex-averaged map was inflated compared to the sex-specific map analysis if only mothers were genotyped and deflated if only fathers were genotyped. The inflation of the lod score when only mothers were genotyped led to markedly increased false-positive rates in some cases. The opposite was true when the recombination rate was higher in males; the EMLOD was inflated if only fathers were genotyped, and deflated if only mothers were genotyped. While the effects of missing parental genotypes were mitigated for less extreme cases of missingness, our results suggest that when possible, sex-specific maps should be used in linkage analyses. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interactionINFLAMMATORY BOWEL DISEASES, Issue 1 2005Marie Pierik MD Abstract Background and Aims: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 × smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. Patients and Methods: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. Results: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P , 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). Conclusions: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4. [source] Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1INFLAMMATORY BOWEL DISEASES, Issue 3 2004Jin Hong Low Abstract Genome-wide scans have implicated several susceptibility loci, but linkage of 19p13 (IBD6) to Crohn's disease (CD) has not been fully replicated. We report a replication study of IBD6 in a UK Caucasian population. Two hundred eighty-four affected sibling pairs from 234 families were used for the linkage study. Linkage between IBD6 linkage and CD was replicated (LOD score = 1.59). Two candidate genes (DDXL and ICAM-1) within the IBD6 locus were examined in a case/control study with a total of 228 CD and 243 ulcerative colitis (UC) patients and 407 healthy controls. No association to either UC or CD was found in three novel intronic single nucleotide polymorphisms (SNPs) in DDXL. For ICAM-1, a significant association was found between K469 homozygosity and CD overall (39.9% vs 29.4%; Pc = 0.0096) and between E469 and fistulating disease (21.8% vs 10.0%, Pc = 0.030). In the UC group, limited disease extent was associated with homozygosity of the G241 allele (82.7% vs 64.7%, Pc = 0.0040). These data support linkage for CD at 19p13 and suggest that the amino acid polymorphisms in ICAM-1 may be associated with IBD. [source] Alcoholism Susceptibility Loci: Confirmation Studies in a Replicate Sample and Further MappingALCOHOLISM, Issue 7 2000Tatiana Foroud Background: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: Additional, genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-III-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets. [source] Linkage analysis of schizophrenia to chromosome 15AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 8 2001Dr. Pablo V. Gejman Abstract We have mapped a sample of 68 families consisting of one or more affected sibling pairs with schizophrenia or schizoaffective disorder with 20 markers spanning all of chromosome 15 to investigate whether there is a locus on chromosome 15 that confers an increased susceptibility to schizophrenia using parametric and nonparametric linkage analyses. Allele sharing identical by descent and multipoint maximum likelihood score (MLS) statistics were employed. Results show excess allele sharing for multiple markers in 15q11.2,q25, a chromosomal region previously found linked to a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, a decrease associated with schizophrenia. Excess allele sharing was found for markers spanning about 48 cM in 15q11.2,q25 (D15S1002,D15S1023). The greatest single point allele sharing was found at D15S659 (62.6%). The multipoint MLS scores were greater than 1.0 in the 30,52 cM interval delimited by ACTC and D15S150, with a maximum value of 2.0 with GENEHUNTER PLUS near D15S1039. © 2001 Wiley-Liss, Inc. [source] A genomewide linkage study of age at onset in schizophrenia,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 5 2001Alastair G. Cardno Abstract There is strong evidence for a genetic contribution to age at onset of schizophrenia, which probably involves both susceptibility loci for schizophrenia and modifying loci acting independent of disease risk. We sought evidence of linkage to loci that influence age at onset of schizophrenia in a sample of 94 affected sibling pairs with DSM-IV schizophrenia or schizoaffective disorder, and age at first psychiatric contact of 45 years or less. Individuals were genotyped for 229 microsatellite markers spaced at approximately 20 cM intervals throughout the genome. Loci contributing to age at onset were sought by a quantitative maximum-likelihood multipoint linkage analysis using MAPMAKER/SIBS. A nonparametric multipoint analysis was also performed. The genomewide significance of linkage results was assessed by simulation studies. There were six maximum-likelihood LOD score peaks of 1.5 or greater, the highest being on chromosome 17q (LOD,=,2.54; genomewide P,=,0.27). This fulfils Lander and Kruglyak's [1995: Nat Genet 11:241,247] criteria for suggestive linkage in that it would be expected to occur once or less (0.3 times) per genome scan. However, this finding should be treated with caution because the LOD score appeared to be almost solely accounted for by the pattern of ibd sharing at one marker (D17S787), with virtually no evidence of linkage over flanking markers. None of the linkage results achieved genomewide statistical significance, but the LOD score peak on chromosome 13q (LOD,=,1.68) coincided with the region showing maximum evidence for linkage in the study by Blouin et al. [1998: Nat Genet 20:70,73] of categorical schizophrenia. © 2001 Wiley-Liss, Inc. [source] Familial associations of intense preoccupations, an empirical factor of the restricted, repetitive behaviors and interests domain of autismTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 8 2009Christopher J. Smith Background:, Clinical heterogeneity of autism likely hinders efforts to find genes associated with this complex psychiatric disorder. Some studies have produced promising results by restricting the sample according to the expression of specific familial factors or components of autism. Previous factor analyses of the restricted, repetitive behaviors and interest (RRBI) domain of autism have consistently identified a two-factor model that explains a moderate amount of variance. The identification of additional factors may explain more variance in the RRBI domain and provide an additional component of autism that may help in the identification of underlying genetic association. Methods:, We conducted factor analyses of RRBI symptoms with a sample that included verbal subjects meeting full criteria for autism aged 5 to 22 years (n = 245). Among affected sibling pairs (n = 126) we examined the familial aggregation of the identified factors. We also examined the associations of the factors with autism-related personality traits in fathers and mothers (n = 50). Results:, The previously identified two-factor model , insistence on sameness (IS) and repetitive stereotypic motor behaviors (RSMB) , was replicated in our sample. Next, a second factor analysis that included the item for verbal rituals resulted in a four-factor model , IS, ,simple' RSMB, ,complex' RSMB, and a fourth factor including symptoms associated with intense preoccupations (IP). Of these four, both IS and IP were significantly familial among affected siblings, but only IP was significantly correlated with the broader autism phenotype traits of rigidity and aloofness in fathers. Conclusions:, The results support previous evidence for the IS factor, its familiality, and the identification of IP as an additional strong candidate trait for genetic studies of autism. [source] | |||||||||||||