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Tatiana Foroud

Publications and source records attributed to Tatiana Foroud.

At least 37 records · Page 2Linked to original sources
PubMed2006

Association between GABRA1 and drinking behaviors in the collaborative study on the genetics of alcoholism sample.

BACKGROUND: A wealth of literature supports the role of gamma-aminobutyric acid (GABA) in neurobiological pathways contributing to alcohol dependence and related phenotypes. Animal studies have consistently tied rodent homologs of the GABAA receptor genes on human chromosome 5q to alcohol-related behaviors; however, human studies have produced mixed results. Family-based association analyses previously conducted in the Collaborative Study on the Genetics of Alcoholism (COGA) sample yielded no evidence of association with Diagnostic and Statistical Manual of Mental Disorder-fourth edition (DSM-IV) alcohol dependence and these genes. As a follow-up to that study, we examined several alcohol-related behaviors in the COGA sample as follows: (1) a broader definition of alcohol dependence, including DSM-III-R symptoms and Feighner criteria (referred to as COGA alcohol dependence); (2) withdrawal; (3) history of alcohol-induced blackouts; (4) level of response to alcohol; (5) age of onset of regular drinking; and (6) age at first drunkenness. METHODS: Family-based association tests were conducted, using multiple single-nucleotide polymorphisms (SNPs) in each of the 4 GABAA receptor genes on chromosome 5q. RESULTS: In GABRA1, we found evidence of association with several of the drinking behavior phenotypes, including COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. We did not find consistent evidence of association with the remaining genes and any of the phenotypes. CONCLUSIONS: We found evidence for association between GABRA1 and COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. These analyses suggest that efforts to characterize genetic contributions to alcohol dependence may benefit by examining alcohol-related behaviors in addition to clinical alcohol dependence diagnoses.

Age of Onset↗
PubMed2006

Marital status, alcohol dependence, and GABRA2: evidence for gene-environment correlation and interaction.

OBJECTIVE: The gene GABRA2 has been associated with the risk for alcohol dependence in independent samples. This article explores how this genetic risk factor interacts with marital status, another factor previously shown to be associated with the risk for alcohol dependence. METHOD: Data from more than 1,900 male and female subjects from the Collaborative Study of the Genetics of Alcoholism (COGA) sample were analyzed. Subjects were recruited based on membership in a family with multiple individuals with alcoholism. A series of analyses was performed to evaluate the relationship between the following: (1) GABRA2 and alcohol dependence, (2) marital status and alcohol dependence, (3) GABRA2 and marital status, and (4) interactions between GABRA2 and marital status on the development of alcohol dependence in the high-risk COGA sample. Additional analyses were carried out in a sample of approximately 900 individuals from control families to test the generalizability of results. RESULTS: Both GABRA2 and marital status contributed independently to the development of alcohol dependence in the COGA sample. The high-risk genotype at GABRA2 was also related to a decreased likelihood of marrying and an increased likelihood of divorce, which appeared to be mediated in part by personality characteristics. There was also differential risk associated with the GABRA2 genotype according to marital status. CONCLUSIONS: These analyses provide evidence of both gene-environment correlation and gene-environment interaction associated with GABRA2, marital status, and alcohol dependence. They illustrate the complex pathways by which genotype and environmental risk factors act and interact to influence alcohol dependence and challenge traditional conceptualizations of "environmental" risk factors.

Adolescent↗
PubMed2005

Standard linkage and association methods identify the mechanism of four susceptibility genes for a simulated complex disease.

The simulated dataset of the Genetic Analysis Workshop 14 provided affection status and the presence or absence of 12 traits. It was determined that all affected individuals must have traits E, F and H (EFH phenotype) and they must also have either trait B (B subtype) or traits C, D, and G (CDG subtype). A genome screen was performed, and linkage peaks were identified on chromosomes 1, 3, 5, and 9 using microsatellite markers. Dense panels of single-nucleotide polymorphism (SNP) markers were ordered for each of the four linkage peaks. In each case, association analyses identified a single SNP that accounted for the linkage evidence. The SNP on chromosome 1 appeared to primarily influence the B subtype, while the SNPs on chromosomes 5 and 9 primarily influenced the CDG subtype. The chromosome 3 SNP had the strongest effect and influenced both subtypes, as well as the requisite EFH phenotype. Recognizing the two subtypes prior to linkage analysis was key to identifying these loci using only a single replicate. This highlights the need in real life situations for careful examination of the phenotypic data prior to genetic analysis.

Chromosome Mapping↗
PubMed2005

Endophenotypes successfully lead to gene identification: results from the collaborative study on the genetics of alcoholism.

The use of endophenotypes has been proposed as a strategy to aid gene identification efforts for complex phenotypes [Gottesman, I. I., and Shields J. (1972). Schizophrenia and Genetics: A Twin Study Vantage Point. London: Academic]. As part of the Collaborative Study of the Genetics of Alcoholism (COGA) project, we have analyzed electrophysiological endophenotypes, in addition to clinical diagnoses, as part of our effort to identify genes involved in the predisposition to alcohol dependence. In this paper we summarize published results from linkage and association analyses of two chromosomal regions in which the use of endophenotypes has successfully led to the identification of genes associated with alcohol dependence [GABRA2 (Edenberg et al., (2004). Am. J. Hum. Genet. 74:705-714) and CHRM2 (Wang et al., (2004). Hum. Mol. Genet. 13:1903-1911)]. Our experience in the COGA project has been that the analysis of endophenotypes provides several advantages over diagnostic phenotypes, including the strength and localization of the linkage signal. Our results provide an illustration of the successful use of endophenotypes to identify genes involved in the predisposition to a complex psychiatric phenotype, a strategy originally proposed by Gottesman and Shields in 1972.

Alcoholism↗
PubMed2005

Functional variant in a bitter-taste receptor (hTAS2R16) influences risk of alcohol dependence.

A coding single-nucleotide polymorphism (cSNP), K172N, in hTAS2R16, a gene encoding a taste receptor for bitter beta -glucopyranosides, shows significant association with alcohol dependence (P = .00018). This gene is located on chromosome 7q in a region reported elsewhere to exhibit linkage with alcohol dependence. The SNP is located in the putative ligand-binding domain and is associated with an increased sensitivity to many bitter beta -glucopyranosides in the presence of the N172 allele. Individuals with the ancestral allele K172 are at increased risk of alcohol dependence, regardless of ethnicity. However, this risk allele is uncommon in European Americans (minor-allele frequency [MAF] 0.6%), whereas 45% of African Americans carry the allele (MAF 26%), which makes it a much more significant risk factor in the African American population.

Black or African American↗
PubMed2005

Genome screen for bone mineral density phenotypes in Fisher 344 and Lewis rat strains.

In humans, peak bone mineral density (BMD) is the primary determinant of osteoporotic fracture risk among older individuals, with high peak BMD levels providing protection against osteoporosis in the almost certain event of bone loss later in life. A genome screen to identify quantitative trait loci (QTLs) contributing to areal BMD (aBMD) and volumetric BMD (vBMD) measurements at the lumbar spine and femoral neck was completed in 595 female F2 rats produced from reciprocal crosses of inbred Fischer 344 and Lewis rats. Significant evidence of linkage was detected to rat Chromosomes 1, 2, 8, and 10, with LOD scores above 8.0. The region on rat Chromosome 8 is syntenic to human Chromosome 15, where linkage to spine and femur BMD has been previously reported and confirmed in a sample of premenopausal women.

Animals↗
PubMed2005

A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

Aminopeptidases↗
PubMed2005

Analysis of variation in expression of autosomal dominant osteopetrosis type 2: searching for modifier genes.

INTRODUCTION: Autosomal Dominant Osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. Analysis of ADO2 in our pedigrees indicates that the penetrance is 66%, with a highly variable phenotype. METHODS: To identify genes that modify disease status, we performed a 10 cM genome-wide scan using 400 microsatellite markers in 112 subjects from our 8 largest ADO2 families with mutations in the ClCN7 gene. Results were analyzed by parametric linkage analysis using autosomal dominant and recessive models for affects on disease status. Follow-up genotyping with additional microsatellite markers was performed for regions with LOD scores over 1.5. In addition, we compared the frequency of two nonsynonymous SNPs, rs12926089 (V418M) and rs11559208 (K691E), and one promoter SNP rs960467 in the normal ClCN7 allele between a sample of unaffected gene carriers and clinically affected subjects to test the hypothesis that genetic variation in the non-disease allele within the ClCN7 gene might influence disease expression. RESULTS: We found potential evidence of linkage for a modifier gene(s) on 9q21-22 with a LOD score of 1.89, which is not statistically significant, but interesting. We also found that, for SNP V418M on the non-disease allele with the wild-type ClCN7 sequence, 94.92% (56/59) of clinically affected subjects and 78.13% (25/32) of unaffected gene carriers had a valine while 5.08% (3/59) of the affected subjects and 21.88% (7/32) of unaffected gene carriers had a methionine (P < 0.03). Unfortunately, SNP K691E was not informative in our families. For SNP rs960467, on the non-disease allele with the wild-type ClCN7 gene, 87.93% (51/58) of clinically affected subjects and 62.50% (20/32) of unaffected gene carriers had a C allele while 12.07% (7/58) of the clinically affected subjects and 37.50% (12/32) of unaffected gene carriers had a T allele (P < 0.007). As expected, the polymorphisms on the disease allele were not associated with disease status. CONCLUSIONS: Chromosome 9q21-22 may harbor a modifier gene(s) that affect(s) ADO2 disease status and severity. Additionally, we find the associations between the polymorphisms on the non-disease allele and unaffected gene carrier status.

Alleles↗
PubMed2005

Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Bipolar Disorder↗
PubMed2005

Whole-genome scan for linkage to bone strength and structure in inbred Fischer 344 and Lewis rats.

UNLABELLED: A genome-wide genetic linkage analysis identified several chromosomal regions influencing bone strength and structure in F2 progeny of Fischer 344 x Lewis inbred rats. INTRODUCTION: Inbred Fischer 344 (F344) and Lewis (LEW) rats are similar in body size, but the F344 rats have significantly lower BMD and biomechanical strength of the femur and spine compared with LEW rats. The goal of this study was to identify quantitative trait loci (QTL) linked to bone strength and structure in adult female F2 rats from F344 and LEW progenitors. MATERIALS AND METHODS: The 595 F2 progeny from F344 x LEW rats were phenotyped for measures of bone strength (ultimate force [Fu]; energy to break [U]; stiffness [S]) of the femur and lumbar vertebra and structure (femur midshaft polar moment of inertia [Ip]; femur midshaft cortical area; vertebral area). A genome-wide scan was completed in the F2 rats using 118 microsatellite markers at an average interval of 20 cM. Multipoint quantitative linkage analysis was performed to identify chromosomal regions that harbor QTL for bone strength and structure phenotypes. RESULTS: Evidence of linkage for femur and lumbar strength was observed on chromosomes (Chrs) 1, 2, 5, 10, and 19. Significant linkage for femoral structure was detected on Chrs 2, 4, 5, 7, and 15. QTLs affecting femoral strength on Chrs 2 and 5 were also found to influence femur structure. Unique QTLs on Chrs 1, 10, and 19 were found that contributed to variability in bone strength but had no significant effect on structure. Also, unique QTLs were observed on Chrs 4, 7, and 15 that affected only bone structure without any effect on biomechanics. CONCLUSION: We showed multiple genetic loci influencing bone strength and structure in F344 x LEW F2 rats. Some of these loci are homologous to mouse and human chromosomes previously linked to related bone phenotypes.

Animals↗
PubMed2005

The Familial Intracranial Aneurysm (FIA) study protocol.

BACKGROUND: Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 20,000 people per year in the U.S. annually and nearly half of the affected persons are dead within the first 30 days. Survivors of ruptured IAs are often left with substantial disability. Thus, primary prevention of aneurysm formation and rupture is of paramount importance. Prior studies indicate that genetic factors are important in the formation and rupture of IAs. The long-term goal of the Familial Intracranial Aneurysm (FIA) Study is to identify genes that underlie the development and rupture of intracranial aneurysms (IA). METHODS/DESIGN: The FIA Study includes 26 clinical centers which have extensive experience in the clinical management and imaging of intracerebral aneurysms. 475 families with affected sib pairs or with multiple affected relatives will be enrolled through retrospective and prospective screening of potential subjects with an IA. After giving informed consent, the proband or their spokesperson invites other family members to participate. Each participant is interviewed using a standardized questionnaire which covers medical history, social history and demographic information. In addition blood is drawn from each participant for DNA isolation and immortalization of lymphocytes. High- risk family members without a previously diagnosed IA undergo magnetic resonance angiography (MRA) to identify asymptomatic unruptured aneurysms. A 10 cM genome screen will be performed to identify FIA susceptibility loci. Due to the significant mortality of affected individuals, novel approaches are employed to reconstruct the genotype of critical deceased individuals. These include the intensive recruitment of the spouse and children of deceased, affected individuals. DISCUSSION: A successful, adequately-powered genetic linkage study of IA is challenging given the very high, early mortality of ruptured IA. Design features in the FIA Study that address this challenge include recruitment at a large number of highly active clinical centers, comprehensive screening and recruitment techniques, non-invasive vascular imaging of high-risk subjects, genome reconstruction of dead affected individuals using marker data from closely related family members, and inclusion of environmental covariates in the statistical analysis.

Clinical Protocols↗
PubMed2005

Sex-specific and non-sex-specific quantitative trait loci contribute to normal variation in bone mineral density in men.

INTRODUCTION: A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In women peak BMD is highly heritable and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed to establish the heritability of peak BMD, identify QTL contributing to normal variation in BMD, and determine which QTL might be sex specific. METHODS: BMD at the spine and hip were measured in 323 pairs of brothers aged 18-61 yr (264 white pairs; 59 black pairs). Heritability was calculated and linkage analysis performed with spine and hip BMD phenotypes. RESULTS: Heritability estimates ranged from 0.61 to 0.87 and were not significantly different between white and black men. A 9-cM genome-wide scan followed by genotyping with more closely spaced markers identified suggestive QTL (logarithm of the odds > 2.2) for BMD on chromosomes 1q (spine), 2p (spine), 2q (hip), 14p (spine), 18 (hip), and 21 (hip). Comparison with published data in 774 pairs of premenopausal sisters suggested that the QTL on 1q (spine), 2q (hip), 14p (spine), and 21q (hip) were male specific, whereas those on 2p (spine) and 18 (hip) were not sex specific. CONCLUSIONS: This study demonstrates that BMD in healthy men is highly heritable with similar estimates of the genetic contribution to BMD in both whites and blacks. Of the six QTL identified, three were specific for spine BMD and three were specific for hip BMD. When compared with published QTL for peak BMD in women from the same geographical region, four of the QTL appeared to be male specific. The occurrence of sex-specific genes in humans for BMD has potentially important implications for the pathogenesis and treatment of osteoporosis.

Adolescent↗
PubMed2005

No association of the GABAA receptor genes on chromosome 5 with alcoholism in the collaborative study on the genetics of alcoholism sample.

A substantial body of literature suggests that gamma-aminobutyric acid (GABA) may be involved in the neurochemical pathways contributing to alcohol use and related disorders. Chromosome 5 contains a cluster of GABA(A) receptor genes, GABRA1, GABRA6, GABRB2, and GABRG2, which have been among the most extensively studied in relation to alcohol use. These studies have yielded mixed results. Using data from large, multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA), we sought to provide more conclusive evidence regarding the role of the GABA(A) receptor genes on chromosome 5. Multiple single nucleotide polymorphisms (SNPs) were tested in each of the four chromosome 5q GABA(A) receptor genes, and we conducted both classic trio-based association analyzes and extended pedigree analyzes. We found no consistent evidence of association with alcohol dependence or alcohol dependence comorbid with antisocial personality disorder (ASPD) for any of the regions tested in the chromosome 5 GABA(A) receptor genes. These analyses suggest that the GABA(A) receptor genes on chromosome 5 do not play a strong role in alcohol dependence. Future studies are planned to test whether these genes are more important in influencing behavioral endophenotypes related to the risk of alcohol dependence.

Alcoholism↗
PubMed2005

Sex-specific quantitative trait loci contribute to normal variation in bone structure at the proximal femur in men.

Bone structure is an important determinant of osteoporotic fracture. In women, bone structure is highly heritable, and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed at establishing the heritability of bone structure at the proximal femur, identifying QTL contributing to normal variation in bone structure, and determining which QTL might be sex-specific. Bone structure at the proximal femur was measured in 205 pairs of brothers age 18-61. Heritability was calculated, and linkage analysis performed on phenotypes at the proximal femur. Heritability estimates ranged from 0.99 to 0.39. A genome wide scan identified suggestive QTL (LOD>2.2) for femoral shaft width on chromosome 14q (LOD=2.69 at position 99 cM), calcar femorale at chromosome 2p (LOD=3.97 at position 194 cM) and at the X chromosome (LOD=3.01 at position 77 cM), femoral neck width on chromosome 5p (LOD=2.28 at position 0 cM), femoral head width on chromosome 11q (LOD=2.30 at position 131 cM) and 15q (LOD=3.11 at position 90 cM), and pelvic axis length on chromosome 4q (LOD=4.16 at position 99 cM) and 17q (LOD=2.80 at position 112 cM). Comparison with published data in 437 pairs of premenopausal sisters from the same geographical region suggested that 3 of the 7 autosomal QTL were male-specific. This study demonstrates that bone structure at the proximal femur in healthy men is highly heritable. The occurrence of sex-specific genes in humans for bone structure has important implications for the pathogenesis and treatment of osteoporosis.

Adult↗
PubMed2005

Expression profiling and QTL analysis: a powerful complementary strategy in drug abuse research.

Alcoholism is a complex disease exhibiting a multifactorial mode of transmission. To simplify the genetic and phenotypic complexity of the alcoholic phenotype, alcohol-preferring (P) and -non-preferring (NP) rats were developed on the basis of alcohol preference and consumption as an animal model of alcoholism. Total gene expression analysis (TOGA) and quantitative trait loci (QTL) analysis were applied to selectively bred, inbred P and NP rats as complementary studies to identify genetic factors that contribute to alcohol preference and consumption. TOGA analysis was utilized to screen for differential expression in several brain regions involved in the mesocorticolimbic dopamine (DA) system. Genes exhibiting differences in expression were then screened for an association to the alcohol preference phenotype, the quantitative trait of a previously identified QTL. By evaluating differences in gene expression for linkage to a quantitative trait, this combined approach was implemented to identify alpha-synuclein, a candidate gene for alcohol preference.

Animals↗
PubMed2004

Contribution of the LRP5 gene to normal variation in peak BMD in women.

UNLABELLED: The role of the LRP5 gene in rare BMD-related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5 and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5 in our sample. INTRODUCTION: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been implicated as the cause of multiple distinct BMD-related rare Mendelian phenotypes. We sought to examine whether the LRP5 gene contributes to the observed variation in peak BMD in the normal population. MATERIALS AND METHODS: We genotyped 12 single nucleotide polymorphisms (SNPs) in LRP5 using allele-specific PCR and mass spectrometry methods. Linkage disequilibrium between the genotyped LRP5 SNPs was measured. We tested for association between these SNPs and both hip and spine BMD (adjusted for age and body weight) in 1301 healthy premenopausal women who took part in a sibling pair study aimed at identifying the genes underlying peak bone mass. Our study used both population-based (ANOVA) and family-based (quantitative transmission disequilibrium test) association methodology. RESULTS AND CONCLUSIONS: The linkage disequilibrium pattern and haplotype block structure within the LRP5 gene were consistent with that observed in other studies. Although significant evidence of association was found between LRP5 SNPs and both hip and spine BMD, only a small proportion of the total variation in these phenotypes was accounted for. The genotyped SNPs accounted for approximately 0.8% of the variation in femoral neck BMD and 1.1% of the variation in spine BMD. Results from our sample suggest that natural variation in and around LRP5 is not a major contributor to the observed variability in peak BMD at either the femoral neck or lumbar spine in white women.

Adult↗
PubMed2004

Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees.

BACKGROUND: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p. METHODS: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed. RESULTS: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2. CONCLUSIONS: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.

Bipolar Disorder↗