Biomedical subjects

Tatiana Foroud

Publications and source records attributed to Tatiana Foroud.

At least 55 records · Page 3Linked to original sources

PubMed2004

False positive rates in association studies as a function of degree of stratification.

UNLABELLED: To explore the degree to which stratification can cause spurious positive association results, we tested for association between BMD and 373 genetic markers using 381 white and 126 black females. The rate of positive results doubled as the proportion of stratification increased, showing the importance of controlling for stratification in association studies. INTRODUCTION: Population-based association studies are commonly used to test the relationship between polymorphisms in a candidate gene and a disease or trait of interest. Although the collection of samples for this type of study design is relatively cost-effective, the statistical analysis may be susceptible to false positive results because of the effects of population stratification. Such results may occur when the underlying populations differ in both the polymorphism allele frequency and mean trait value. MATERIALS AND METHODS: To explore the degree to which stratification can cause spurious positive association results, we analyzed femoral neck BMD data from an unrelated sample of 381 white and 126 black premenopausal females. As part of a previous genome screen, 373 microsatellite markers had been genotyped for each individual. For simplicity of interpretation, each multiallelic marker was reduced to a biallelic marker, with the most common allele as one allele and all other alleles combined as the second allele. As expected, the black women differed substantially for marker allele frequencies and had significantly higher mean femoral neck BMD than their white counterparts. Random subsets of the white and black samples were sampled, with increasing proportions of stratification (0%, 1%, 2%, 5%, 10%, 15%, and 20% black subjects) in the total analyzed sample. ANOVA was used to test for association between the recoded marker and femoral neck BMD. RESULTS AND CONCLUSIONS: The rate of positive results for the association test were observed to double as the proportion of stratification increased, with substantial increases in the frequency of false positives even for stratification proportions as small as 2-5%. These results show the importance of controlling for stratification when the trait and the polymorphism allele frequency differ between the races.

Adult↗

PubMed2004

Peak bone mineral density at the hip is linked to chromosomes 14q and 15q.

A major determinant of osteoporotic hip fracture is peak hip BMD which is a highly heritable trait. Caucasian American women have lower BMD and higher hip fracture rates than African American women. This study examines linkage of hip BMD in 570 Caucasian sister pairs and 204 African American sister pairs. It compares the results with our published study in a smaller overlapping sample of Caucasian sisters. Hip BMD was measured at neck, trochanter, Ward's, shaft, and total hip. Principal component analysis provided a novel BMD phenotype comprising neck and trochanter, common sites of fracture, and Ward's, site of lowest BMD. A 9 cM genome scan was performed for these phenotypes. Significant linkage was found at chromosomes 14q and 15q. At 14q, the 774 African American and Caucasian sister pairs together yielded the highest LOD score for trochanter (3.5) and at 15q the highest LOD score for femoral neck (4.3). This linkage study in Caucasian and African American healthy premenopausal sisters demonstrates that chromosomes 14q and 15q harbor genes that affect peak bone mass at the hip in women. Principal component had comparable LOD scores with those of the component phenotypes suggesting pleiotropic effects of these genes on hip phenotypes.

Adult↗

PubMed2004

Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.

Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P=.000000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.

Alcoholism↗

PubMed2004

A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence.

Smoking is a highly heritable, addictive disorder that commonly co-occurs with alcohol dependence. The purpose of this study is to perform a genomic screen for habitual smoking and comorbid habitual smoking and alcohol dependence in families from the Collaborative Study on the Genetics of Alcoholism (COGA). Subjects were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) to evaluate alcohol dependence and habitual smoking (smoking one pack per day or more for at least 6 months). Sixty seven multi-generational families with 154 independent sibling pairs affected with habitual smoking were genotyped in a screening sample. Analyses on 79 multi-generational families with 173 independent sibling pairs were repeated in a replication sample. Sibpair analyses were performed using ASPEX. Four chromosomal regions in the screening sample had increased allele sharing among sibling pairs for habitual smoking with a LOD score greater than 1 (chromosomes 5, 9, 11, and 21). The highest LOD score was on chromosome 9 (LOD = 2.02; allele sharing 58.9%). Four chromosomal regions also had modest evidence for linkage to the comorbid phenotype habitual smoking and alcohol dependence (chromosomes 1, 2, 11, 15); and the strongest finding was on chromosome 2 (LOD = 3.30; allele sharing 69.1%). Previously identified areas (chromosomes 1 and 7) implicated in the development of alcohol dependence in this same data set did not provide evidence for linkage to habitual smoking in the screening sample. In the replication data set, there continued to be increased allele sharing near peaks identified in the screening sample on chromosomes 2 and 9, but the results were modest. An area on chromosome 7, approximately 60 cM from a location previously identified in linkage analysis with alcohol dependence, had increased allele sharing for the comorbid habitual smoking and alcohol dependence. These data provide evidence of specific genetic regions involved in the development of habitual smoking and not alcohol dependence. Conversely, genetic regions that influence the development of alcohol dependence do not appear to contribute to the development of habitual smoking. Finally, there is also evidence of an area on chromosome 2 that may reflect a common genetic vulnerability locus to both habitual smoking and alcohol dependence.

Adolescent↗

PubMed2004

Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.

Adolescent↗

PubMed2004

Linkage and linkage disequilibrium of evoked EEG oscillations with CHRM2 receptor gene polymorphisms: implications for human brain dynamics and cognition.

Event-related oscillations (ERO) offer an alternative theoretical and methodological approach to the analysis of event-related EEG responses. The P300 event-related potential (ERP) is elicited through the superposition of the delta (1-3 Hz) and theta (3-7 Hz) band oscillatory responses. The cholinergic neurotransmitter system has a key function in modulating excitatory post-synaptic potentials caused by glutamate, and therefore influences P300 generation and the underlying oscillatory responses. Here we report significant linkage and linkage disequilibrium between target case frontal theta band, visual evoked brain oscillations and a single nucleotide polymorphism (SNP) from the cholinergic muscarinic receptor gene (CHRM2) on chromosome 7. We also demonstrate significant linkage disequilibrium between CHRM2 SNPs and target case parietal delta band visual evoked oscillations (LD P<0.001). These findings were not observed for the equivalent non-target case data, suggesting a role for the CHRM2 gene in higher cognitive processing in humans.

Adolescent↗

PubMed2004

Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging.

Living to a late age without suffering any major health problems is a genetically influenced trait. To identify the genes contributing to this important phenotype, a 10 cM genome screen was performed in 95 pairs of male fraternal twins concordant for healthy aging. Individuals meeting these criteria were defined as those attaining the age of 70 free of cardiovascular disease (coronary surgery, diabetes, heart attack, and stroke) and prostate cancer. Six chromosomal regions were identified with logarithm of odds (LOD) scores greater than 1.2 (p<.01). A region on chromosome 4 at marker D4S1564 produced a LOD score of 1.67; this was the same marker previously linked to extreme longevity segregating as an autosomal dominant trait in centenarian families. Our results provide independent evidence that a locus on the long arm of chromosome 4 is associated with better physical aging and/or longevity.

Aged↗

PubMed2004

Association of GABRG3 with alcohol dependence.

BACKGROUND: Evidence from human, animal, and in vitro cell models suggests that gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABAA receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive. METHODS: We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABAA receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABAA receptor genes: GABRA5, GABRB3, and GABRG3. RESULTS: Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes. CONCLUSIONS: These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA.

Alcoholism↗

PubMed2004

The search for genetic risk factors associated with suicidal behavior.

BACKGROUND: Suicide and suicidal behavior are prevalent among individuals with psychiatric disorders, including alcohol dependence. A genome screen was performed in multiplex alcohol dependent families ascertained as part of the Collaborative Study on the Genetics of Alcoholism to identify chromosomal regions of interest related to two types of suicidal behavior: suicide attempts and suicidality. METHODS: Sibling pair analyses were used to conduct linkage analyses using both qualitative and quantitative suicide-related phenotypes. The qualitative trait of "suicide attempts" was examined using 59 affected sibling pairs. The quantitative trait of "suicidality" was examined using all possible 1366 sibling pairs and 705 independent sibling pairs. RESULTS: For the qualitative phenotype suicide attempts, chromosome 2 yielded a maximum lod score of 4.2. For the quantitative suicidality index, a maximum lod score of 1.8 was observed on chromosome 3, and a lod score of 1.5 was found on chromosome 1. CONCLUSIONS: This study represents the first genome-wide scan of suicidal behavior. Significant evidence of linkage was found on chromosome 2 for the phenotype suicide attempts, the same chromosomal region previously reported to be linked to alcohol dependence in this sample. This finding does not seem to be due solely to an association between suicide and alcohol dependence. There was more modest evidence of linkage to chromosomes 1 and 3 for suicidality; however, these findings did not reach statistical significance. There was no overlap in findings for these two phenotypes of suicidal behavior.

Alcoholism↗

PubMed2004

Glutathione S-transferase 8-8 expression is lower in alcohol-preferring than in alcohol-nonpreferring rats.

OBJECTIVE: A primary focus of alcohol research is to provide novel targets for alcohol treatment by identifying genes that predispose individuals to drink alcohol. Animal models of alcoholism developed by selective breeding are invaluable tools to elucidate both the genetic nature and the underlying biological mechanisms that contribute to alcohol dependence. These selected lines (high alcohol preferring and low alcohol preferring) display phenotypic and genetic differences that can be studied to further our understanding of alcohol preference and related genetic traits. By combining molecular techniques, genetic and physiological factors that underlie the cause of alcoholism can be identified. METHODS: Total gene expression analysis was used to identify genes that are differentially expressed in specific brain regions between alcohol-naive, inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats. Quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot, and sequence analysis were used to further characterize rat glutathione S-transferase 8-8 (rGST 8-8). RESULTS: Lower expression of rGST 8-8 mRNA was observed in discrete brain regions of iP compared with iNP animals, and these expression differences were confirmed. To determine additional expression patterns of rGST 8-8, we used in situ hybridization. Rat GST 8-8 was highly expressed in hippocampus, the choroid plexus of the dorsal third ventricle and the lateral ventricle, and ependymal cells along the dorsal third ventricle and the third ventricle. Western blot analysis showed that rGST 8-8 protein levels were lower in the hippocampus and the amygdala of iP compared with iNP. A silent single-nucleotide polymorphism in the coding region and three single-nucleotide polymorphisms in the 3'-UTR were identified in the rGST 8-8 cDNA. CONCLUSION: There is regional variation of rGST 8-8 expression in the brain, at both the mRNA and protein level, and the iP strain has lower innate rGST 8-8 levels than the iNP strain in discrete brain regions.

Alcohol Drinking↗

PubMed2004

Genetics of Parkinson disease.

Parkinson disease (PD) is the second most common neurodegenerative disorder. Recent studies have consistently demonstrated that in some families, disease is attributable to a mutation in a single gene. To date, genetic analyses have detected linkage to six chromosomal regions and have identified three causative genes: PARK1 (alpha-synuclein), PARK2 (parkin), and PARK7 (DJ-1). In addition, mutations in several other genes have been implicated in familial PD. Identification of the mutations in these genes has led to the recognition that the ubiquitin-proteasome system is an important pathway that may be disrupted in PD. Studies are ongoing to identify additional genes that may contribute to PD susceptibility, particularly in late-onset families without a clear pattern of disease inheritance. With the identification of mutations in particular genes and the likely role of additional genes that are important in PD risk-susceptibility, appropriate protocols must be developed so that accurate and informative genetic counseling can be offered to families in which one or more members has PD. Further diagnostic testing should be delayed until more is learned about the frequency, penetrance, and risk assessment of certain gene mutations. Important lessons can be learned from the implementation of counseling protocols for other neurodegenerative disorders, such as Huntington disease and Alzheimer disease.

Genetic Counseling↗

PubMed2003

Identification of genes for complex disease using longitudinal phenotypes.

Using the simulated data set from Genetic Analysis Workshop 13, we explored the advantages of using longitudinal data in genetic analyses. The weighted average of the longitudinal data for each of seven quantitative phenotypes were computed and analyzed. Genome screen results were then compared for these longitudinal phenotypes and the results obtained using two cross-sectional designs: data collected near a single age (45 years) and data collected at a single time point. Significant linkage was obtained for nine regions (LOD scores ranging from 5.5 to 34.6) for six of the phenotypes. Using cross-sectional data, LOD scores were slightly lower for the same chromosomal regions, with two regions becoming nonsignificant and one additional region being identified. The magnitude of the LOD score was highly correlated with the heritability of each phenotype as well as the proportion of phenotypic variance due to that locus. There were no false-positive linkage results using the longitudinal data and three false-positive findings using the cross-sectional data. The three false positive results appear to be due to the kurtosis in the trait distribution, even after removing extreme outliers. Our analyses demonstrated that the use of simple longitudinal phenotypes was a powerful means to detect genes of major to moderate effect on trait variability. In only one instance was the power and heritability of the trait increased by using data from one examination. Power to detect linkage can be improved by identifying the most heritable phenotype, ensuring normality of the trait distribution and maximizing the information utilized through novel longitudinal designs for genetic analysis.

Cardiovascular Diseases↗

PubMed2003

Genome scan of the fifty-six bipolar pedigrees from the NIMH genetics initiative replication sample: chromosomes 4, 7, 9, 18, 19, 20, and 21.

The NIMH genetics initiative on bipolar disorder was established to collect uniformly ascertained bipolar pedigrees for genetic studies. In 1997, the four participating sites published a genome scan on the initial set of 97 bipolar pedigrees. Fifty-six additional bipolar pedigrees have now been ascertained and evaluated. This replication pedigree set contains 354 genotyped subjects, including 139 bipolar I (BPI) subjects, five schizoaffective bipolar type SA/BP subjects, 41 bipolar II (BPII) subjects, and 43 recurrent unipolar (RUP) depression subjects. Our site has recently genotyped the replication study bipolar pedigrees using 107 microsatellite markers from chromosomes 4, 7, 9, 18, 19, 20, and 21. We are now reporting parametric and nonparametric linkage results from this effort. Multipoint nonparametric linkage analysis produced three candidate regions with allele sharing LOD scores >/= 1.0. The linkage signal on 4q35 peaked between markers D4S3335 and D4S2390 with an allele sharing LOD score of 2.49. This finding exceeds standard criteria for suggestive linkage. Two additional loci approach suggestive linkage levels: the 4q32 finding had its maximum near marker D4S1629 with an allele sharing LOD score of 2.16, and the 20p12 finding peaked at D20S162 with an allele sharing LOD score of 1.82. Multipoint parametric linkage analysis produced similar findings. When we combined the genotype data from the original and the replication pedigree sets, 20p12 yielded a nonparametric LOD score of 2.38, which exceeds standard criteria for suggestive linkage, and a corresponding parametric HLOD score of 2.98. The combined analysis did not provide further support for linkage to 4q32 and 4q35.

Bipolar Disorder↗

PubMed2003

Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families.

Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD=2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD=4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD=2.4) and X (LOD=3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.

Alleles↗

PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Bipolar Disorder↗

PubMed2003

Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative.

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.

Bipolar Disorder↗

PubMed2003

Genome scan of a second wave of NIMH genetics initiative bipolar pedigrees: chromosomes 2, 11, 13, 14, and X.

As part of the on-going NIMH Genetics Initiative on Bipolar Disorder, we have ascertained 153 multiplex bipolar pedigrees and genotyped them in two waves. We report here the genome scan results for chromosomes 2, 11, 13, 14, and X in the second wave of 56 families. A total of 354 individuals were genotyped and included in the current analyses, including 5 with schizoaffective/bipolar (SA/BP), 139 with bipolar I disorder (BPI), 41 with bipolar II disorder (BPII), and 43 with recurrent unipolar depression (RUP). Linkage analyses were carried out with multi-point parametric and non-parametric affected relative pair methods using three different definitions of the affected phenotype: (model 1) SA/BP and BPI; (model 2) SA/BP, BPI, and BPII; and (model 3) SA/BP, BPI, BPII, and RUP. The best findings were on 11p15.5 (NPL = 2.96, P = 0.002) and Xp11.3 (NPL = 2.19, P = 0.01). These findings did not reach conventional criteria for significance, but they were located near regions that have been identified in previous genetic studies of bipolar disorder. The relatively modest but consistent findings across studies may suggest that these loci harbor susceptibility genes of modest effect in a subset of families. Large samples such as that being collected by the NIMH Initiative will be necessary to examine the heterogeneity and identify these susceptibility genes.

Bipolar Disorder↗

PubMed2003

Linkage mapping of beta 2 EEG waves via non-parametric regression.

Parametric linkage methods for analyzing quantitative trait loci are sensitive to violations in trait distributional assumptions. Non-parametric methods are relatively more robust. In this article, we modify the non-parametric regression procedure proposed by Ghosh and Majumder [2000: Am J Hum Genet 66:1046-1061] to map Beta 2 EEG waves using genome-wide data generated in the COGA project. Significant linkage findings are obtained on chromosomes 1, 4, 5, and 15 with findings at multiple regions on chromosomes 4 and 15. We analyze the data both with and without incorporating alcoholism as a covariate. We also test for epistatic interactions between regions of the genome exhibiting significant linkage with the EEG phenotypes and find evidence of epistatic interactions between a region each on chromosome 1 and chromosome 4 with one region on chromosome 15. While regressing out the effect of alcoholism does not affect the linkage findings, the epistatic interactions become statistically insignificant.

Adolescent↗