Familial aggregation and genome-wide linkage analysis of carotid artery plaque: the NHLBI family heart study

OBJECTIVE: To evaluate familial and genetic influences on carotid artery plaque, a qualitative marker of the systemic burden of atherosclerosis. METHODS: The design was a cross-sectional study of 2,223 members of 525 randomly-ascertained families and 2,514 members of 589 high coronary heart disease (CHD) risk families from 4 U.S. communities. RESULTS: The prevalence of plaque was 33, 36, and 47%, respectively, among probands with 0, 1, and 2 or more first-degree relatives with a history of CHD. There was evidence of sibling aggregation of plaque in random families (OR = 1.89; 95% CI: 1.44, 2.48), but associations were substantially attenuated when adjusted for major cardiovascular disease risk factors. A genome scan with 420 microsatellite markers revealed no regions of significant or suggestive linkage for plaque in 342 affected sibling pairs, although suggestive linkage (LOD score: 2.43) was found on chromosome 2p11.2 (D2S1790) in pairs aged 55 years or younger. Other markers with nominal evidence for linkage (p < 0.05) were found on chromosomes 2p25, 2q24-q32, 6q21-q23, 7p12-p21, 7q11-q21, 8q24, 12q12-q13, 18p11, 21q21 and Xp11, Xq12, and Xq24. CONCLUSIONS: There was modest familial aggregation of carotid artery plaque, but a genome-wide scan indicated no regions of significant or suggestive linkage.     

Quantitative trait loci influencing low density lipoprotein particle size in African Americans

Genomic regions that influence LDL particle size in African Americans are not known. We performed family-based linkage analyses to identify genomic regions that influence LDL particle size and also exert pleiotropic effects on two closely related lipid traits, high density lipoprotein cholesterol (HDL-C) and triglycerides, in African Americans. Subjects (n = 1,318, 63.0 +/- 9.5 years, 70% women, 79% hypertensive) were ascertained through sibships with two or more individuals diagnosed with essential hypertension before age 60. LDL particle size was measured by polyacrylamide gel electrophoresis, and triglyceride levels were log-transformed to reduce skewness. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Univariate and bivariate linkage analyses were performed using a variance components approach. LDL particle size was highly heritable (h(2) = 0.78) and significantly (P < 0.0001) genetically correlated with HDL-C (rho(G) = 0.32) and log triglycerides (rho(G) = -0.43). Significant evidence of linkage for LDL particle size was present on chromosome 19 [85.3 centimorgan (cM), log of the odds (LOD) = 3.07, P = 0.0001], and suggestive evidence of linkage was present on chromosome 12 (90.8 cM, LOD = 2.02, P = 0.0011). Bivariate linkage analyses revealed tentative evidence for a region with pleiotropic effects on LDL particle size and HDL-C on chromosome 4 (52.9 cM, LOD = 2.06, P = 0.0069). These genomic regions may contain genes that influence interindividual variation in LDL particle size and potentially coronary heart disease susceptibility in African Americans.     

Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families

High plasma apolipoprotein B (apoB) and LDL cholesterol levels increase cardiovascular disease risk. These highly correlated measures may be partially controlled by common genetic polymorphisms. To identify chromosomal regions that contain genes causing low plasma levels of one or both parameters in Caucasian families ascertained for familial hypobetalipoproteinemia (FHBL), we conducted a whole-genome scan using 443 microsatellite markers typed in nine multigenerational families with at least two members with FHBL. Both variance components and regression-based linkage methods were used to identify regions of interest. Common linkage regions were identified for both measures on chromosomes 10q25.1-10q26.11 [maximum log of the odds (LOD) = 4.2 for LDL and 3.5 for apoB] and 6q24.3 (maximum LOD = 1.46 for LDL and 1.84 for apoB). There was also evidence for linkage to apoB on chromosome 13q13.2 (LOD = 1.97) and to LDL on chromosome 3p14.1 at 94 centimorgan (LOD = 1.52). Bivariate linkage analysis provided further evidence for loci contributing to both traits (6q24.3, LOD = 1.43; 10q25.1, LOD = 1.74). We evaluated single nucleotide polymorphisms (SNPs) in genes within our linkage regions to identify variants associated with apoB or LDL levels. The most significant finding was for rs2277205 in the 5' untranslated region of acyl-coenzyme A dehydrogenase short/branched chain and LDL (P = 10(-7)). Three additional SNPs were associated with apoB and/or LDL (P < 0.01). Although only the linkage signal on chromosome 10 reached genome-wide statistical significance, there are likely multiple chromosomal regions with variants that contribute to low levels of apoB and LDL and that may protect against coronary heart disease.     

Linkage analysis of adult height with parent-of-origin effects in the Framingham Heart Study

Current linkage analysis methods for quantitative traits do not usually incorporate imprinting effects. Here, we carried out genome-wide linkage analysis for loci influencing adult height in the Framingham Heart Study subjects using variance components while allowing for imprinting effects. We used a sex-averaged map for the 22 autosomes, while chromosomes 6, 14, 18, and 19 were also analyzed using sex-specific maps. We compared results from these four analyses: 1) non-imprinted with sex-averaged maps, 2) imprinted with sex-averaged maps, 3) non-imprinted with sex-specific maps, and 4) imprinted with sex-specific maps. We found four regions on three chromosomes (14q32, 18p11-q21, 18q21-22, and 19q13) with LOD scores above 2.0, with a maximum LOD score of 3.12, allowing for imprinting and sex-specific maps, at D18S1364 on 18q21. While we obtained significant evidence of imprinting effects in both the 18p11-q21 and 19q13 regions when using sex-averaged maps, there were no significant differences between the imprinted and non-imprinted LOD scores when we used sex-specific maps. Our results illustrate the importance of allowing for gender-specific effects in linkage analyses, whether these are in the form of gender-specific recombination frequencies, or in the form of imprinting effects.     

Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study

Previous studies have demonstrated that low density lipoprotein cholesterol (LDL-C) concentration is influenced by both genes and environment. Although rare genetic variants associated with Mendelian causes of increased LDL-C are known, only one common genetic variant has been identified, the apolipoprotein E gene (APOE). In an attempt to localize quantitative trait loci (QTLs) influencing LDL-C, we conducted a genome-wide linkage scan of LDL-C in participants of the Strong Heart Family Study (SHFS). Nine hundred eighty men and women, age 18 years or older, in 32 extended families at three centers (in Arizona, Oklahoma, and North and South Dakota) were phenotyped for LDL-C concentration and other risk factors. Using a variance component approach and the program SOLAR, and after accounting for the effects of covariates, we detected a QTL influencing LDL-C on chromosome 19, nearest marker D19S888 at 19q13.41 [logarithm of odds (LOD) = 4.3] in the sample from the Dakotas. This region on chromosome 19 includes many possible candidate genes, including the APOE/C1/C4/C2 gene cluster. In follow-up association analyses, no significant evidence for an association was detected with the APOE*2 and APOE*4 alleles (P = 0.76 and P = 0.53, respectively). Suggestive evidence of linkage to LDL-C was detected on chromosomes 3q, 4q, 7p, 9q, 10p, 14q, and 17q. These linkage signals overlap positive findings for lipid-related traits and harbor plausible candidate genes for LDL-C.     

Neuropsychological endophenotype approach to genome-wide linkage analysis identifies susceptibility loci for ADHD on 2q21.1 and 13q12.11

ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities > 0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores > or = 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders.     

Applying novel genome-wide linkage strategies to search for loci influencing type 2 diabetes and adult height in American Samoa

Type 2 diabetes mellitus (T2DM) is a common complex phenotype that by the year 2010 is predicted to affect 221 million people globally. In the present study we performed a genome-wide linkage scan using the allele-sharing statistic Sall implemented in Allegro and a novel two-dimensional genome-wide strategy implemented in Merloc that searches for pairwise interaction between genetic markers located on different chromosomes linked to T2DM. In addition, we used a robust score statistic from the newly developed QTL-ALL software to search for linkage to variation in adult height. The strategies were applied to a study sample consisting of 238 sib-pairs affected with T2DM from American Samoa. We did not detect any genome-wide significant susceptibility loci for T2DM. However, our two-dimensional linkage investigation detected several loci pairs of interest, including 11q22 and 21q21, 9q21 and 11q22, 1p22-p21 and 4p15, and 4p15 and 15q11-q14, with a two-loci maximum LOD score (MLS) greater than 2.00. Most detected individual loci have previously been identified as susceptibility loci for diabetes-related traits. Our two-dimensional linkage results may facilitate the selection of potential candidate genes and molecular pathways for further diabetes studies because these results, besides providing candidate loci, also demonstrate that polygenic effects may play an important role in T2DM. Linkage was detected (p value of 0.005) for variation in adult height on chromosome 9q31, which was reported previously in other populations. Our finding suggests that the 9q31 region may be a strong quantitative trait locus for adult height, which is likely to be of importance across populations.     

Pleiotropic QTL on chromosome 12q23-q24 influences triglyceride and high-density lipoprotein cholesterol levels: the HERITAGE family study

To determine whether a common quantitative trait locus (QTL) influences the variation of fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels, we used a bivariate multipoint linkage analysis with 654 polymorphic markers in 99 white and 101 black families. The phenotypes were investigated under two conditions: at baseline and after a 20-week exercise training intervention. A maximum genome-wide bivariate LOD score of 3.0 (p = 0.00010) was found on chromosome 12q23-q24, located within the IGF1 gene (insulin-like growth factor 1, at 107 cM) for TG and HDL-C at baseline in whites. This bivariate linkage peak is considerably higher than the univariate linkage results at the same chromosome location for either trait (for TG, LOD = 2.07, p = 0.00108; for HDL-C, LOD = 2.04, p = 0.00101). The genetic correlations between baseline TG and HDL-C levels were -0.14 for the residual and -0.33 for the QTL components. Moreover, association analysis showed that TG, HDL-C, and IGF1 are significantly associated (p = 0.04). In conclusion, these results suggest that a QTL on chromosome 12q23-q24 influences the variation of plasma TG and HDL-C levels. Further investigation should confirm whether IGF1 or another nearby gene is responsible for the concomitant variation in TG and HDL-C levels.     

A locus on chromosome 13 influences levels of TAFI antigen in healthy Mexican Americans

When activated, thrombin activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by modifying fibrin, depressing its plasminogen binding potential. Polymorphisms in the TAFI structural gene (CPB2) have been associated with variation in TAFI levels, but the potential occurrence of influential quantitative trait loci (QTLs) located elsewhere in the genome has been explored only in families ascertained in part through probands affected by thrombosis. We report the results of the first genome-wide linkage screen for QTLs that influence TAFI phenotypes. Data are from 635 subjects from 21 randomly ascertained Mexican American families participating in the San Antonio Family Heart Study. Potential QTLs were localized through a genome-wide multipoint linkage scan using 417 highly informative autosomal short tandem repeat markers spaced at approximately 10-cM intervals. We observed a maximum multipoint LOD score of 3.09 on chromosome 13q, the region of the TAFI structural gene. A suggestive linkage signal (LOD = 2.04) also was observed in this region, but may be an artifact. In addition, weak evidence for linkage occurred on chromosomes 17p and 9q. Our results suggest that polymorphisms in the TAFI structural gene or its nearby regulatory elements may contribute strongly to TAFI level variation in the general population, although several genes in other regions of the genome may also influence variation in this phenotype. Our findings support those of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, which identified a potential TAFI QTL on chromosome 13q in a genome-wide linkage scan in Spanish thrombophilia families.     

Genome-wide Study of Families with Absolute Pitch Reveals Linkage to 8q24.21 and Locus Heterogeneity

Absolute pitch (AP) is the rare ability to instantaneously recognize and label tones with their musical note names without using a reference pitch for comparison. The etiology of AP is complex. Prior studies have implicated both genetic and environmental factors in its genesis, yet the molecular basis for AP remains unknown. To locate regions of the human genome that may harbor AP-predisposing genetic variants, we performed a genome-wide linkage study on 73 multiplex AP families by genotyping them with 6090 SNP markers. Nonparametric multipoint linkage analyses were conducted, and the strongest evidence for linkage was observed on chromosome 8q24.21 in the subset of 45 families with European ancestry (exponential LOD score = 3.464, empirical genome-wide p = 0.03). Other regions with suggestive LOD scores included chromosomes 7q22.3, 8q21.11, and 9p21.3. Of these four regions, only the 7q22.3 linkage peak was also evident when 19 families with East Asian ancestry were analyzed separately. Though only one of these regions has yet reached statistical significance individually, we detected a larger number of independent linkage peaks than expected by chance overall, indicating that AP is genetically heterogeneous.     

Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Quebec Family Study

A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Québec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method. In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage.     

Linkage at 12q24 with systemic lupus erythematosus (SLE) is established and confirmed in Hispanic and European American families

Systemic lupus erythematosus (SLE) is a chronic, complex, and systemic human autoimmune disease, with both an environmental component and a heritable predisposition. Clinical studies, reinforced by epidemiology and genetics, show impressive variation in disease severity, expression, prevalence, and incidence by ethnicity and sex. To identify the novel SLE susceptibility loci, we performed a genomewide scan with 318 markers on 37 multiplex Hispanic families, using a nonparametric penetrance-independent affected-only allele-sharing method. Three chromosomal regions (12q24, 16p13, and 16q12-21) exceeded our predetermined threshold (Zlr>2.32; nominal P<.01) for further evaluation. Suspected linkages at 12q24, 16p13, and 16q12-21 were tested in an independent data set consisting of 92 European American (EA-1) and 55 African American (AA) families. The linkage at 12q24 was replicated in EA-1 (Zlr=3.06; P=.001) but not in AA (Zlr=0.37; P=.35). Although neither the 16p13 nor the 16q12-21 was confirmed in EA-1 or AA, the suggestive linkage (Zlr=3.06; P=.001) at 16q12-21 is sufficient to confirm the significant linkage, reported elsewhere, at this location. The evidence for linkage at 12q24 in the 129 combined (Hispanic and EA-1) families exceeded the threshold for genomewide significance (Zlr=4.39; P=5.7x10-6; nonparametric LOD=4.19). Parametric linkage analyses suggested a low-penetrance, dominant model (LOD=3.72). To confirm the linkage effect at 12q24, we performed linkage analysis in another set of 82 independent European American families (EA-2). The evidence for linkage was confirmed (Zlr=2.11; P=.017). Therefore, our results have detected, established, and confirmed the existence of a novel SLE susceptibility locus at 12q24 (designated "SLEB4") that may cause lupus, especially in Hispanic and European American families.     

Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing "suggestive" or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.     

Susceptibility Loci for Adiposity Phenotypes on 8p, 9p,and 16q in American Samoa and Samoa

Obesity is a complex phenotype affected by genetic and environmental influences such as sociocultural factors and individual behaviors. Previously, we performed two separate genome‐wide investigations for adiposity‐related traits (BMI, percentage body fat (%BF), abdominal circumference (ABDCIR), and serum leptin and serum adiponectin levels) in families from American Samoa and in families from Samoa. The two polities have a common evolutionary history but have lately been influenced by variations in economic development, leading to differences in income and wealth and in dietary and physical activity patterns. We now present a genome‐wide linkage scan of the combined samples from the two polities. We adjust for environmental covariates, including polity of residence, education, cigarette smoking, and farm work, and use variance component methods to calculate univariate and bivariate multipoint lod scores. We identified a region on 9p22 with genome‐wide significant linkage for the bivariate phenotypes ABDCIR–%BF (1‐d.f. lod 3.30) and BMI–%BF (1‐d.f. lod 3.31) and two regions with genome‐wide suggestive linkage on 8p12 and 16q23 for adiponectin (lod 2.74) and the bivariate phenotype leptin‐ABDCIR (1‐d.f. lod 3.17), respectively. These three regions have previously been reported to be linked to adiposity‐related phenotypes in independent studies. However, the differences in results between this study and our previous polity‐specific studies suggest that environmental effects are of different importance in the samples. These results strongly encourage further genetic studies of adiposity‐related phenotypes where extended sets of carefully measured environmental factors are taken into account.     

The genetic architecture of lipoprotein subclasses in Gullah-speaking African American families enriched for type 2 diabetes: The Sea Islands Genetic African American Registry (Project SuGAR)

We sought to partition the genetic and environmental influences on lipoprotein subclasses and identify genomic regions that may harbor genetic variants that influence serum lipoprotein levels in a sample of Gullah-speaking African-Americans. We genotyped 5,974 SNPs in 979 subjects from 418 pedigrees and used the variance component approach to compute heritability estimates, genetic and environmental correlations, and linkage analyses for selected lipoprotein subclasses. The highest heritability estimate was observed for large VLDL particle concentration (0.56 ± 0.14). Mean LDL particle size and small LDL particle concentration (−0.94) had the strongest genetic correlation estimate. The highest logarithm of odds (LOD) score detected (3.0) was on chromosome 6p24 for small LDL particle concentration. The strongest signal, obtained with the reduced sample of diabetic individuals only, was observed on chromosome 20p13 for small LDL particle concentration. The highest bivariate linkage signal (LOD 2.4) was observed on chromosome 6p24 for mean LDL particle size and small LDL particle concentration.jlr Our results suggest a significant genetic contribution to multiple lipoprotein subclasses studied in this sample and that novel loci on chromosomes 6, 10, 16, and 20 may harbor genes contributing to small, atherogenic LDL particle concentration and large, triglyceride-rich VLDL particle concentration.     

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.     

Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD

Obsessive compulsive disorder (OCD) has a complex etiology that encompasses both genetic and environmental factors. However, to date, despite the identification of several promising candidate genes and linkage regions, the genetic causes of OCD are largely unknown. The objective of this study was to conduct linkage studies of childhood-onset OCD, which is thought to have the strongest genetic etiology, in several OCD-affected families from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The authors used parametric and non-parametric approaches to conduct genome-wide linkage analyses using 5,786 single nucleotide repeat polymorphisms (SNPs) in three CVCR families with multiple childhood-onset OCD-affected individuals. We identified areas of suggestive linkage (LOD score ≥ 2) on chromosomes 1p21, 15q14, 16q24, and 17p12. The strongest evidence for linkage was on chromosome 15q14 (LOD = 3.13), identified using parametric linkage analysis with a recessive model, and overlapping a region identified in a prior linkage study using a Caucasian population. Each CVCR family had a haplotype that co-segregated with OCD across a ~7 Mbp interval within this region, which contains 18 identified brain expressed genes, several of which are potentially relevant to OCD. Exonic sequencing of the strongest candidate gene in this region, the ryanodine receptor 3 (RYR3), identified several genetic variants of potential interest, although none co-segregated with OCD in all three families. These findings provide evidence that chromosome 15q14 is linked to OCD in families from the CVCR, and supports previous findings to suggest that this region may contain one or more OCD susceptibility loci.     

A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans

Epidemiological studies have demonstrated that genetic factors account for at least 50% of the liability for nicotine dependence (ND). Although several linkage studies have been conducted, all samples to date were primarily of European origin. In this study, we conducted a genomewide scan of 1,261 individuals, representing 402 nuclear families, of African American (AA) origin. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and S.A.G.E. programs, we found a region near marker D10S1432 on chromosome 10q22 that showed a significant linkage to indexed SQ, with a maximum LOD score of 4.17 at 92 cM and suggestive linkage to HSI, SQ, and log-transformed SQ. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 and D13S788. Other locations on chromosomes 15p11, 17q25, and 18q12 exhibited some evidence of linkage for ND (LOD >1.44). The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. Some of these regions have been linked to smoking behavior at nominally significant levels in other studies, which provides independent replication of the regions for ND in different cohorts. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Further analysis of these positive regions by fine mapping and/or association analysis is thus warranted. To our knowledge, this study represents the first genomewide linkage scan of ND in an AA sample.     

Genetic loci for blood lipid levels identified by linkage and association analyses in Caribbean Hispanics

To identify genetic loci influencing blood lipid levels in Caribbean Hispanics, we first conducted a genome-wide linkage scan in 1,211 subjects from 100 Dominican families on five lipid quantitative traits: total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), and LDL-C/HDL-C ratio. We then investigated the association between blood lipid levels and 21,361 single nucleotide polymorphisms (SNP) under the 1-logarithm of odds (LOD) unit down regions of linkage peaks in an independent community-based subcohort (N = 814, 42% Dominican) from the Northern Manhattan Study (NOMAS). We found significant linkage evidence for LDL-C/HDL-C on 7p12 (multipoint LOD = 3.91) and for TC on 16q23 (LOD = 3.35). In addition, we identified suggestive linkage evidence of LOD > 2.0 on 15q23 for TG, 16q23 for LDL-C, 19q12 for TC and LDL-C, and 20p12 for LDL-C. In the association analysis of the linkage peaks, we found that seven SNPs near FLJ45974 were associated with LDL-C/HDL-C with a nominal P < 3.5 × 10(-5), in addition to associations (P < 0.0001) for other lipid traits with SNPs in or near CDH13, SUMF2, TLE3, FAH, ARNT2, TSHZ3, ZNF343, RPL7AL2, and TMC3. Further studies are warranted to perform in-depth investigations of functional genetic variants in these regions.     

A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans

Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P<.0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P<.0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LOD(eq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LOD(eq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.