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ABSTRACT: The alcohol-preferring (P) and -nonpreferring (NP) rat lines were developed using bidirectional selective breeding for alcohol consumption (g/kg/day) and alcohol preference (water:ethanol ratio). During a preliminary study, we detected a difference in body weight between inbred P (iP) and inbred NP (iNP) rats that appeared to be associated with the transfer of the Chromosome 4 quantitative trait locus (QTL) seen in the P.NP and NP.P congenic strains. After the initial confirmation that iP rats displayed lower body weight when compared to iNP rats (data not shown), body weight and growth rates of each chromosome 4 reciprocal congenic rat strain (P.NP and NP.P) were measured, and their body weight was consistent with their respective donor strain phenotype, confirming that a quantitative trait locus for body weight mapped to the chromosome 4 interval. Utilizing the newly developed interval-specific congenic strains (ISCS-A and ISCS-B), the QTL interval was further narrowed identifying the following candidate genes of interest: neuropeptide Y (Npy), juxtaposed with another zinc finger gene 1 (Jazf1), corticotrophin releasing factor receptor 2 (Crfr2) and LanC lantibiotic synthetase component C-like 2 (Lancl2). These findings indicate that a biologically active variant(s) regulates body weight on rat chromosome 4 in iP and iNP rats. This QTL for body weight was successfully captured in the P.NP and NP.P congenic strains, and interval-specific congenic strains (ISCSs) were subsequently employed to fine-map the QTL interval identifying the following candidate genes of interest: Npy, Jazf1, Crfr2 and Lancl2. Both Npy and Crfr2 have been previously identified as candidate genes of interest underlying the chromosome 4 QTL for alcohol consumption in iP and iNP rats.
Alcohol (Fayetteville, N.Y.) 01/2013; 47(1):63-7. · 2.41 Impact Factor
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Tatiana Foroud,
Daniel L Koller, Dongbing Lai,
Laura Sauerbeck,
Craig Anderson,
Nerissa Ko,
Ranjan Deka,
Thomas H Mosley,
Myriam Fornage,
Daniel Woo, [......],
Guy Rouleau,
E Sander Connolly,
Bradford B Worrall,
Dawn Kleindorfer,
Matthew L Flaherty,
Sharyl Martini,
Jason Mackey,
Felipe De Los Rios La Rosa,
Robert D Brown,
Joseph P Broderick
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ABSTRACT: Background- Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA. Method- We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis. RESULTS: There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6 × 10(-8)) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7 × 10(-5)). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype. CONCLUSIONS: In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).
Stroke 09/2012; 43(11):2846-2852. · 5.73 Impact Factor
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ABSTRACT: The High Alcohol Preferring (HAP1) and Low Alcohol Preferring (LAP1) mouse lines were selectively bred for differences in alcohol intake. The HAP1 and LAP1 mice are essentially non-inbred lines that originated from an outbred colony of HS/Ibg mice, a heterogeneous stock developed from intercrossing 8 inbred strains of mice. In a former genomewide SNP association study, we identified quantitative trait loci (QTL) on chromosomes 1, 3, 5, and 9 (Bice et al. 2009). Provisional QTL were also identified on chromosomes 8 and X. In the present study, using the same F2 DNA samples, we placed a much denser set of SNPs within each of those QTL regions. Using the same analytical approach employed previously, which utilizes ancestral recombination to fine map the QLT interval, we obtained significant LOD scores on chromosomes 1, 3, and 9, only. Our results using a dense set of SNP markers suggest that there are multiple loci contributing to alcohol preference on those three chromosomes.
Behavior Genetics 12/2010; 41(4):565-70. · 2.52 Impact Factor
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ABSTRACT: The high and low alcohol-drinking (HAD and LAD) rats were selectively bred for differences in alcohol intake. The HAD/LAD rats originated from the N/Nih heterogeneous stock developed from intercrossing eight inbred rat strains. The HAD×LAD F2 were genotyped, and a powerful analytical approach, using ancestral recombination and F2 recombination, was used to narrow a quantitative trait loci (QTL) for alcohol drinking to a 2-cM region on distal chromosome 10 that was in common in the HAD1/LAD1 and HAD2/LAD2 analyses. Quantitative real-time PCR was used to examine mRNA expression of six candidate genes (Crebbp, Trap1, Gnptg, Clcn7, Fahd1, and Mapk8ip3) located within the narrowed QTL region in the HAD1/LAD1 rats. Expression was examined in five brain regions, including the nucleus accumbens, amygdala, caudate putamen, hippocampus, and prefrontal cortex. All six genes showed differential expression in at least one brain region. Of the genes tested in this study, Crebbp and Mapk8ip3 may be the most promising candidates with regard to alcohol drinking.
Alcohol (Fayetteville, N.Y.) 09/2010; 44(6):477-85. · 2.41 Impact Factor
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Daniel L Koller,
Shoji Ichikawa, Dongbing Lai,
Leah R Padgett,
Kimberly F Doheny,
Elizabeth Pugh,
Justin Paschall,
Siu L Hui,
Howard J Edenberg,
Xiaoling Xuei,
Munro Peacock,
Michael J Econs,
Tatiana Foroud
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ABSTRACT: Several genome-wide association studies (GWAS) have been performed to identify genes contributing to bone mineral density (BMD), typically in samples of elderly women and men.
The objective of the study was to identify genes contributing to BMD in premenopausal women.
GWAS using the Illumina 610Quad array in premenopausal European-American (EA) women and replication of the top 50 single-nucleotide polymorphisms (SNPs) for two BMD measures in African-American (AA) women.
Subjects included 1524 premenopausal EA women aged 20-45 yr from 762 sibships and 669 AA premenopausal women aged 20-44 yr from 383 sibships.
There were no interventions.
BMD was measured at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry. Age- and weight-adjusted BMD values were tested for association with each SNP, with P values determined by permutation.
SNPs in CATSPERB on chromosome 14 provided evidence of association with femoral neck BMD (rs1298989, P = 2.7 x 10(-5); rs1285635, P = 3.0 x 10(-5)) in the EA women, and some supporting evidence was also observed with these SNPs in the AA women (rs1285635, P = 0.003). Genes identified in other BMD GWAS studies, including IBSP and ADAMTS18, were also among the most significant findings in our GWAS.
Evidence of association to several novel loci was detected in a GWAS of premenopausal EA women, and SNPs in one of these loci also provided supporting evidence in a sample of AA women.
The Journal of clinical endocrinology and metabolism 02/2010; 95(4):1802-9. · 6.50 Impact Factor
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ABSTRACT: Bone mineral density (BMD) achieved during young adulthood (peak BMD) is one of the major determinants of osteoporotic fracture in later life. Genetic variants associated with BMD have been identified by three recent genome-wide association studies. The most significant single-nucleotide polymorphisms (SNPs) from these studies were genotyped to test whether they were associated with peak BMD in premenopausal American women. Femoral neck and lumbar spine BMD were determined by dual-energy X-ray absorptiometry in two groups of premenopausal women: 1524 white women and 512 black women. In premenopausal white women, two SNPs in the C6orf97/ESR1 region were significantly associated with BMD (p < 4.8 x 10(-4)), with suggestive evidence for CTNNBL1 and LRP5 (p < .01). Evidence of association with one of the two SNPs in the C6orf97/ESR1 region also was observed in premenopausal black women. Furthermore, SNPs in SP7 and a chromosome 4 intergenic region showed suggestive association with BMD in black women. Detailed analyses of additional SNPs in the C6orf97/ESR1 region revealed multiple genomic blocks independently associated with femoral neck and lumbar spine BMD. Findings in the three published genome-wide association studies were replicated in independent samples of premenopausal American women, suggesting that genetic variants in these genes or regions contribute to peak BMD in healthy women in various populations.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2010; 25(8):1821-9. · 6.04 Impact Factor
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Ranjan Deka,
Daniel L Koller, Dongbing Lai,
Subba Rao Indugula,
Guangyun Sun,
Daniel Woo,
Laura Sauerbeck,
Charles J Moomaw,
Richard Hornung,
E Sander Connolly, [......],
Guy Rouleau,
Irene Meissner,
Joan E Bailey-Wilson,
John Huston,
Robert D Brown,
Dawn O Kleindorfer,
Matthew L Flaherty,
Carl D Langefeld,
Tatiana Foroud,
Joseph P Broderick
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ABSTRACT: The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA.
White probands with an IA from families with multiple affected members were identified by 26 clinical centers located throughout North America, New Zealand, and Australia. White control subjects free of stroke and IA were selected by random digit dialing from the Greater Cincinnati population. SNPs previously associated with IA on chromosomes 2, 8, and 9 were genotyped using a TaqMan assay or were included in the Affymetrix 6.0 array that was part of a genomewide association study of 406 IA cases and 392 control subjects. Logistic regression modeling tested whether the association of replicated SNPs with IA was modulated by smoking.
The strongest evidence of association with IA was found with the 8q SNP rs10958409 (genotypic P=9.2x10(-5); allelic P=1.3x10(-5); OR=1.86, 95% CI: 1.40 to 2.47). We also replicated the association with both SNPs on chromosome 9p, rs1333040 and rs10757278, but were not able to replicate the previously reported association of the 2 SNPs on chromosome 2q. Statistical testing showed a multiplicative relationship between the risk alleles and smoking with regard to the risk of IA.
Our data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking.
Stroke 02/2010; 41(6):1132-7. · 5.73 Impact Factor
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ABSTRACT: A major predictor of age-related osteoporotic fracture is peak areal bone mineral density (aBMD) which is a highly heritable trait. However, few linkage and association studies have been performed in men to identify the genes contributing to normal variation in aBMD. The aim of this study was to perform a genome wide scan in healthy men to identify quantitative trait loci (QTL) that were significantly linked to aBMD and to test whether any of these might be sex-specific.
aBMD at the spine and hip were measured in 515 pairs of brothers, aged 18-61 (405 white pairs, 110 black pairs). Linkage analysis in the brother sample was compared with results in a previously published sample of 774 sister pairs to identify sex-specific quantitative trait loci (QTL).
A genome wide scan identified significant QTL (LOD>3.6) for aBMD on chromosomes 4q21 (hip), 7q34 (spine), 14q32 (hip), 19p13 (hip), 21q21 (hip), and 22q13 (hip). Analysis suggested that the QTL on chromosomes 7q34, 14q32, and 21q21 were male-specific whereas the others were not sex-specific.
This study demonstrates that six QTL were significantly linked with aBMD in men. One was linked to the spine and five were linked to the hip. When compared to published data in women from the same geographical region, the QTL on chromosomes 7, 14 and 21 were male-specific. The occurrence of sex-specific genes in humans for aBMD has important implications for the pathogenesis and treatment of osteoporosis.
Bone 06/2009; 45(3):443-8. · 4.02 Impact Factor
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ABSTRACT: The high and low alcohol preferring (HAP1 and LAP1) mouse lines were selectively bred for differences in alcohol intake. The HAP1 and LAP1 mice are essentially noninbred lines that originated from the outbred colony of HS/Ibg mice, a heterogeneous stock developed from intercrossing 8 inbred strains of mice.
A total of 867 informative SNPs were genotyped in 989 HAP1 x LAP1 F2, 68 F1s, 14 parents (6 LAP1, 8 HAP1), as well as the 8 inbred strains of mice crossed to generate the HS/Ibg colony. Multipoint genome wide analyses were performed to simultaneously detect linked QTLs and also fine map these regions using the ancestral haplotypes.
QTL analysis detected significant evidence of association on 4 chromosomes: 1, 3, 5, and 9. The region on chromosome 9 was previously found linked in a subset of these F2 animals using a whole genome microsatellite screen.
We have detected strong evidence of association to multiple chromosomal regions in the mouse. Several of these regions include candidate genes previously associated with alcohol dependence in humans or other animal models.
Alcoholism Clinical and Experimental Research 01/2009; 33(3):531-7. · 3.34 Impact Factor
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Tatiana Foroud,
Laura Sauerbeck,
Robert Brown,
Craig Anderson,
Daniel Woo,
Dawn Kleindorfer,
Matthew L Flaherty,
Ranjan Deka,
Richard Hornung,
Irene Meissner,
Joan E Bailey-Wilson,
Carl Langefeld,
Guy Rouleau,
E Sander Connolly, Dongbing Lai,
Daniel L Koller,
John Huston,
Joseph P Broderick
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ABSTRACT: Individuals with 1st degree relatives harboring an intracranial aneurysm (IA) are at an increased risk of IA, suggesting genetic variation is an important risk factor.
Families with multiple members having ruptured or unruptured IA were recruited and all available medical records and imaging data were reviewed to classify possible IA subjects as definite, probable or possible IA or not a case. A 6 K SNP genome screen was performed in 333 families, representing the largest linkage study of IA reported to date. A 'narrow' (n = 705 definite IA cases) and 'broad' (n = 866 definite or probable IA) disease definition were used in multipoint model-free linkage analysis and parametric linkage analysis, maximizing disease parameters. Ordered subset analysis (OSA) was used to detect gene x smoking interaction.
Model-free linkage analyses detected modest evidence of possible linkage (all LOD < 1.5). Parametric analyses yielded an unadjusted LOD score of 2.6 on chromosome 4q (162 cM) and 3.1 on chromosome 12p (50 cM). Significant evidence for a gene x smoking interaction was detected using both disease models on chromosome 7p (60 cM; p </= 0.01). Our study provides modest evidence of possible linkage to several chromosomes.
These data suggest it is unlikely that there is a single common variant with a strong effect in the majority of the IA families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms.
BMC Medical Genetics 01/2009; 10:3. · 2.33 Impact Factor
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ABSTRACT: Phenotypic variation in bone mineral density (BMD) among healthy adults is influenced by both genetic and environmental factors. Sequence variations in the adenylate cyclase 10 (ADCY10) gene, which is also called soluble adenylate cyclase, have previously been associated with low spinal BMD in hypercalciuric patients. Since ADCY10 is located in the region linked to spinal BMD in our previous linkage analysis, we tested whether polymorphisms in this gene are also associated with normal BMD variation in healthy adults. Sixteen single-nucleotide polymorphisms (SNPs) distributed throughout ADCY10 were genotyped in two healthy groups of American whites: 1692 premenopausal women and 715 men. Statistical analyses were performed in the two groups to test for association between these SNPs and the femoral neck and lumbar spine areal BMD. We observed significant evidence of association (p < 0.01), with one SNP each in men and women. Genotypes at these SNPs accounted for <1% of hip BMD variation in men but 1.5% of spinal BMD in women. However, adjacent SNPs did not corroborate the association in either men or women. In conclusion, we found a modest association between an ADCY10 polymorphism and the spinal areal BMD in premenopausal white women.
Calcified Tissue International 12/2008; 84(2):97-102. · 2.38 Impact Factor
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Bradford B Worrall,
Tatiana Foroud,
Robert D Brown,
E Sander Connolly,
Richard W Hornung,
John Huston,
Dawn Kleindorfer,
Daniel L Koller, Dongbing Lai,
Charles J Moomaw,
Laura Sauerbeck,
Daniel Woo,
Joseph P Broderick
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ABSTRACT: Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study.
Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (n=91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable).
Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LOD=3.0) and 6 (33 cM; LOD=2.3). In both chromosomal regions, analyses of these same 26 families considering only IA as the disease phenotype produced LOD scores of 1.8 and 1.6, respectively.
Our linkage analysis in these 26 families using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, supports the concept of shared genetic risk. The chromosome 11 locus appears to confirm earlier independent associations in IA and AA. The chromosome 6 finding is novel. Both warrant further investigation.
Stroke 11/2008; 40(1):71-6. · 5.73 Impact Factor
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Shoji Ichikawa,
Daniel L Koller,
Leah R Curry, Dongbing Lai,
Xiaoling Xuei,
Elizabeth W Pugh,
Ya-Yu Tsai,
Kimberly F Doheny,
Howard J Edenberg,
Siu L Hui,
Tatiana Foroud,
Munro Peacock,
Michael J Econs
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ABSTRACT: Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporotic fractures is peak BMD obtained during young adulthood. We previously reported linkage of chromosome 1q (LOD = 4.3) with variation in spinal areal BMD in healthy premenopausal white women. In this study, we used a two-stage genotyping approach to identify genes in the linked region that contributed to the variation of femoral neck and lumbar spine areal BMD. In the first stage, 654 SNPs across the linked region were genotyped in a sample of 1309 premenopausal white women. The most significant evidence of association for lumbar spine (p = 1.3 x 10(-6)) was found with rs1127091 in the GATAD2B gene. In the second stage, 52 SNPs around this candidate gene were genotyped in an expanded sample of 1692 white women. Significant evidence of association with spinal BMD (p < 10(-5)), and to a lesser extent with femoral neck BMD, was observed with eight SNPs within a single 230-kb linkage disequilibrium (LD) block. The most significant SNP (p = 3.4 x 10(-7)) accounted for >2.5% of the variation in spinal BMD in these women. The 230-kb LD block contains 11 genes, but because of the extensive LD, the specific gene(s) contributing to the variation in BMD could not be determined. In conclusion, the significant association between spinal BMD and SNPs in the 230-kb LD block in chromosome 1q indicates that genetic factor(s) in this block plays an important role in peak spinal BMD in healthy premenopausal white women.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2008; 23(10):1680-8. · 6.04 Impact Factor
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Kang Chu,
Daniel L Koller,
Shoji Ichikawa,
Richard Snyder,
Leah Curry, Dongbing Lai,
Anthony Austin,
Xiaoling Xuei,
Howard J Edenberg,
Siu L Hui,
Tatiana M Foroud,
Munro Peacock,
Michael J Econs
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ABSTRACT: Mutations in the chloride channel 7 gene (CLCN7) cause osteopetrosis, and polymorphisms of CLCN7 in the non-disease allele are associated with penetrance of the autosomal dominant osteopetrosis (ADO) phenotype. Studies have also shown an association between CLCN7 polymorphisms and bone mineral density (BMD) in women. However, there is no study to date that has examined whether CLCN7 polymorphisms underlie normal variation of peak BMD in healthy premenopausal white women and in white men.
Six single nucleotide polymorphisms (SNPs) and one variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene were genotyped. Association was tested between CLCN7 gene polymorphisms and both lumbar spine and femoral neck BMD. Healthy premenopausal white sisters (age 33.1+/-7.2, n=1692) and healthy white brothers (age 33.6+/-10.9, n=715) were studied.
No significant association between CLCN7 gene polymorphisms and BMD at the lumbar spine or femoral neck was found in white women or white men.
Genetic variation in the CLCN7 gene is not a major contributor to the variability in peak BMD at the femoral neck and lumber spine in healthy premenopausal white women and in white men.
Bone 09/2008; 43(6):995-8. · 4.02 Impact Factor
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Tatiana Foroud,
Laura Sauerbeck,
Robert Brown,
Craig Anderson,
Daniel Woo,
Dawn Kleindorfer,
Matthew L Flaherty,
Ranjan Deka,
Richard Hornung,
Irene Meissner,
Joan E Bailey-Wilson,
Guy Rouleau,
E Sander Connolly, Dongbing Lai,
Daniel L Koller,
John Huston,
Joseph P Broderick
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ABSTRACT: Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA.
Multiplex families having at least 2 individuals with "definite" or "probable" IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene x smoking (pack-years) interaction.
The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking.
We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene x smoking interaction with 3 of the loci.
Stroke 06/2008; 39(5):1434-40. · 5.73 Impact Factor
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Shoji Ichikawa,
Daniel L Koller,
Michelle L Johnson, Dongbing Lai,
Xiaoling Xuei,
Howard J Edenberg,
Robert F Klein,
Eric S Orwoll,
Siu L Hui,
Tatiana M Foroud,
Munro Peacock,
Michael J Econs
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ABSTRACT: The Alox15 gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12 may contribute to normal variation in BMD.
Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15-lipoxygenase (Alox15) gene was identified as a negative regulator of peak BMD in mice.
To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population- and family-based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18-61 years of age and 1291 premenopausal women 20-50 years of age.
Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052-0.050). Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081).
Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.
Journal of Bone and Mineral Research 05/2006; 21(4):556-64. · 6.37 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Bone 12/2005; 37(5):655-61. · 4.02 Impact Factor
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ABSTRACT: A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor beta gene (ESR2) is located.
The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation.
This was a population-based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene.
The study was conducted at an academic research laboratory and medical center.
A total of 411 healthy men (aged 18-61 yr) and 1291 healthy premenopausal women (aged 20-50 yr) living in Indiana participated in the study.
There were no interventions.
The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine. Results: Significant association of spine BMD was found with three SNPs in men and one SNP in women (P < or = 0.05). The conditional linkage analysis using the ESR2 haplotypes showed that the ESR2 gene accounts for, at most, 18% of the original linkage.
ESR2 polymorphisms are significantly associated with bone mass in both men and women. However, the ESR2 gene is not entirely responsible for our original linkage, and an additional gene(s) in chromosome 14q contributes to the determination of BMD.
Journal of Clinical Endocrinology & Metabolism 12/2005; 90(11):5921-7. · 6.50 Impact Factor
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ABSTRACT: 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.
Bone 10/2005; 37(4):467-73. · 4.02 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Journal of Clinical Endocrinology & Metabolism 05/2005; 90(5):3060-6. · 6.50 Impact Factor
