A genome-wide scan for type 2 diabetes in African-American families reveals evidence for a locus on chromosome 6q

African Americans are at increased risk of type 2 diabetes and many diabetes complications. We have carried out a genome-wide scan for African American type 2 diabetes using 638 affected sibling pairs (ASPs) from 247 families ascertained through impaired renal function to identify type 2 diabetes loci in this high-risk population. Of the 638 ASPs, 210 were concordant for diabetes with impaired renal function. A total of 390 markers, at an average spacing of 9 cM, were genotyped by the Center for Inherited Disease Research (CIDR) as part of the International Type 2 Diabetes Linkage Analysis Consortium. Nonparametric linkage (NPL) analyses conducted using the exponential model implemented in Genehunter Plus provided suggestive evidence for linkage at 6q24-q27 (163.5 cM, logarithm of odds [LOD] 2.26). Multilocus NPL regression analysis identified the 6q locus (D6S1035, LOD 2.67) and two additional regions: 7p (LOD 1.06) and 18q (LOD 0.87) as important in this model. NPL regression-based interaction analyses and ordered subset analyses (OSAs) supported the presence of a locus at chromosome 7p (29-34 cM) in the pedigrees with the earliest mean age of diagnosis of type 2 diabetes (P = 0.009 for interaction, DeltaP = 0.0034 for OSA) and lower mean BMI (P = 0.009 for interaction, DeltaP = 0.070 for OSA). These results provide evidence that genes predisposing African-American individuals to type 2 diabetes are located in the 6q and 7p regions of the genome.     

Genome-wide search for type 2 diabetes/impaired glucose homeostasis susceptibility genes in the Chinese: significant linkage to chromosome 6q21-q23 and chromosome 1q21-q24

This genome-wide search for susceptibility genes to type 2 diabetes/impaired glucose homeostasis (IGH) was performed on a relatively homogeneous Chinese sample with a total number of 257 pedigrees and 385 affected sibpairs. Two regions showed significant linkage to type 2 diabetes/IGH in the Chinese. The region showing linkage to type 2 diabetes/IGH from the entire sample group analysis was located on chromosome 6q21-q23 (128.93 cM, 1-LOD [logarithm of odds] support interval between 124 and 142 cM, according to the Marshfield genetic map), with a maximum likelihood score of 6.23, a nonparametric linkage (all) score of 4.48, and empirical P value <0.001. With a subanalysis based on 101 affected sibpairs with age at diagnosis of type 2 diabetes/IGH <40 years, we detected significant evidence for linkage to chromosome 1q21-q24 (192.1 cM, 1-LOD support interval between 182 and 197 cM), with a maximum likelihood score of 8.91, a nonparametric linkage (all) score of 5.70, and empirical P value <0.001. No interaction was observed between these two regions. Our independent replication of the region on chromosome 1q that has been shown to be linked significantly to type 2 diabetes/IGH in Chinese supports the notion that gene(s) in this region may be universally important in the development of human type 2 diabetes.     

Meta-analysis of genome-wide linkage studies of quantitative lipid traits in families ascertained for type 2 diabetes

Dyslipidemia is a major risk factor for coronary heart disease, which is the predominant cause of mortality in individuals with type 2 diabetes. To date, nine linkage studies for quantitative lipid traits have been performed in families ascertained for type 2 diabetes, individually yielding linkage results that were largely nonoverlapping. Discrepancies in linkage findings are not uncommon and are typically due to limited sample size and heterogeneity. To address these issues and increase the power to detect linkage, we performed a meta-analysis of all published genome scans for quantitative lipid traits conducted in families ascertained for type 2 diabetes. Statistically significant evidence (i.e., P < 0.00043) for linkage was observed for total cholesterol on 7q32.3-q36.3 (152.43-182 cM; P = 0.00004), 19p13.3-p12 (6.57-38.05 cM; P = 0.00026), 19p12-q13.13 (38.05-69.53 cM; P = 0.00001), and 19q13.13-q13.43 (69.53-101.1 cM; P = 0.00033), as well as LDL on 19p13.3-p12 (P = 0.00041). Suggestive evidence (i.e., P < 0.00860) for linkage was also observed for LDL on 19p12-q13.13, triglycerides on 7p11-q21.11 (63.72-93.29 cM), triglyceride/HDL on 7p11-q21.11 and 19p12-q13.13, and LDL/HDL on 16q11.2-q24.3 (65.2-130.4 cM) and 19p12-q13.13. Linkage for lipid traits has been previously observed on both chromosomes 7 and 19 in several unrelated studies and, together with the results of this meta-analysis, provide compelling evidence that these regions harbor important determinants of lipid levels in individuals with type 2 diabetes.     

Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25

We conducted autosomal genome scans to map loci for metabolic syndrome (MES) and related traits in the Hong Kong Family Diabetes Study. We selected 55 families with 137 affected members (121 affected relative pairs) for nonparametric linkage analysis on MES. We also selected 179 families with 897 members (2,127 relative pairs) for variance component-based linkage analyses on seven MES-related traits: waist circumference, systolic and diastolic blood pressure (BP), triglyceride, HDL cholesterol, fasting plasma glucose, and insulin resistance index (insulin resistance index by homeostasis model assessment [HOMA%IR]). Analyses revealed three regions that showed suggestive linkage for MES and also showed overlapping signals for metabolic traits: chromosome 1 at 169.5-181.5 cM (logarithm of odds [LOD] = 4.50 for MES, 3.71 for waist circumference, and 1.24 for diastolic BP), chromosome 2 at 44.1-57.3 cM (LOD = 2.22 for MES, 2.07 for fasting plasma glucose, and 1.29 for diastolic BP), and chromosome 16 at 45.2-65.4 cM (LOD = 1.75 for MES, 1.61 for HOMA%IR, and 1.25 for HDL cholesterol). Other regions that showed suggestive linkages included chromosome 5q for diastolic BP; 2q, 3q, 6q, 9q, 10q, and 17q for triglyceride; 12p, 12q, and 22q for HDL-C; and 6q for HOMA%IR. Simulation studies demonstrated genome-wide significant linkage of the chromosome 1 region to both MES and waist circumference (P(genome-wide) = 0.002 and 0.019, respectively). In summary, we have found a susceptibility locus on chromosome 1q21-q25 involved in the pathogenesis of multiple metabolic abnormalities, in particular obesity. Our results confirm the findings of previous studies on diabetes and related phenotypes. We also suggest the locations of other loci that may contribute to the development of MES in Hong Kong Chinese.     

Genome-wide linkage analysis for severe obesity in french caucasians finds significant susceptibility locus on chromosome 19q

To ascertain whether distinct chromosomal loci existed that were linked to severe obesity, as well as to utilize the increased heritability of this excessive phenotype, we performed a genome-wide scan in severely obese French Caucasians. The 109 selected pedigrees, totaling 447 individuals, required both the proband and a sibling to be severely obese (BMI >or=35 kg/m(2)), and 84.8% of the nuclear families possessed >or=1 morbidly obese sibling (BMI >or=40). Severe and morbid obesity are still relatively rare in France, with rates of 2.5 and 0.6%, respectively. The initial genome scan consisted of 395 evenly spaced microsatellite markers. Six regions were found to have suggestive linkage on 4q, 6cen-q, 17q, and 19q for a BMI >or=35 phenotypic subset, and 5q and 10q for an inclusive BMI >or=27 group. The highest peak on chromosome 19q (logarithm of odds [LOD] = 3.59) was significant by genome scan simulation testing (P = 0.042). These regions then underwent second-stage mapping with an additional set of 42 markers. BMI >or=35 analysis defined regions on 17q23.3-25.1 and 19q13.33-13.43 with an maximum likelihood score LOD of 3.16 and 3.21, respectively. Subsequent pooled data analysis with an additional previous population of 66 BMI >or=35 sib-pairs led to a significant LOD score of 3.8 at the 19q locus (empirical P = 0.023). For more moderate obesity and overweight susceptibility loci, BMI >or=27 analysis confirmed suggestive linkage to chromosome regions 5q14.3-q21.3 (LOD = 2.68) and 10q24.32-26.2 (LOD = 2.47). Plausible positional candidate genes include NR1H2 and TULP2.     

A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q.

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A weak indication for linkage was obtained between the Isl-1 locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or another nearby gene) lies on chromosome 5q should be determined by further analyses.     

Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24

We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a approximately 2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0-180 and HbA(1c)) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82-1.85 for glucose 150 and 180), 1p31 (LOD = 1.28-2.30 for type 2 diabetes and glucose 120-180), and 18p (LOD = 3.07, P = 0.000085 for HbA(1c) and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.     

A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results. GFR aggregates in families with significant heritability (h(2)) in diabetic (h(2) = 0.45, P < 1 x 10(-5)) and nondiabetic (h(2) = 0.36, P < 1 x 10(-3)) relatives. Genetic correlation (r(G) = 0.35) between the GFR of diabetic and nondiabetic relatives was less than one (P = 0.01), suggesting that genes controlling GFR variation in these groups are different. Linkage results supported this interpretation. In diabetic relatives, linkage was strong on chromosome 2q (logarithm of odds [LOD] = 4.1) and suggestive on 10q (LOD = 3.1) and 18p (LOD = 2.2). In nondiabetic relatives, linkage was suggestive on 3q (LOD = 2.2) and 11p (LOD = 2.1). When diabetic and nondiabetic relatives were combined, strong evidence for linkage was found only on 7p (LOD = 4.0). In conclusion, partially distinct sets of genes control GFR variation in relatives with and without diabetes on chromosome 2q, possibly on 10q and 18p in the former, and on 7p in both. None of these genes overlaps with genes controlling variation in urinary albumin excretion.     

A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes

The main hallmark of diabetic nephropathy is elevation in urinary albumin excretion. We performed a genome-wide linkage scan in 63 extended families with multiple members with type II diabetes. Urinary albumin excretion, measured as the albumin-to-creatinine ratio (ACR), was determined in 426 diabetic and 431 nondiabetic relatives who were genotyped for 383 markers. The data were analyzed using variance components linkage analysis. Heritability (h2) of ACR was significant in diabetic (h2=0.23, P=0.0007), and nondiabetic (h2=0.39, P=0.0001) relatives. There was no significant difference in genetic variance of ACR between diabetic and nondiabetic relatives (P=0.16), and the genetic correlation (rG=0.64) for ACR between these two groups was not different from 1 (P=0.12). These results suggested that similar genes contribute to variation in ACR in diabetic and nondiabetic relatives. This hypothesis was supported further by the linkage results. Support for linkage to ACR was suggestive in diabetic relatives and became significant in all relatives for chromosome 22q (logarithm of odds, LOD=3.7) and chromosome 7q (LOD=3.1). When analyses were restricted to 59 Caucasian families, support for linkage in all relatives increased and became significant for 5q (LOD=3.4). In conclusion, genes on chromosomes 22q, 5q and 7q may contribute to variation in urinary albumin excretion in diabetic and nondiabetic individuals.     

Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25

We conducted an autosomal genome scan to map loci for type 2 diabetes in a Hong Kong Chinese population. We studied 64 families, segregating type 2 diabetes, of which 57 had at least one member with an age at diagnosis of 0.59, P(pointwise) < 0.05): chromosome 1 at 173.9 cM (LOD = 3.09), chromosome 3 at 26.3 cM (LOD = 1.27), chromosome 4 at 135.3 cM (LOD = 2.63), chromosome 5 at 139.3 cM (LOD = 0.84), chromosome 6 at 178.9 cM (LOD = 1.91), chromosome 12 at 48.7 cM (LOD = 1.99), and chromosome 18 at 28.1 cM (LOD = 1.00). Simulation studies showed genome-wide significant evidence for linkage of the chromosome 1 region (P(genome-wide) = 0.036). We have confirmed the results of previous studies for the presence of a susceptibility locus on chromosome 1q21-q25 (173.9 cM) and suggest the locations of other loci that may contribute to the development of type 2 diabetes in Hong Kong Chinese.     

Genome-wide linkage in three Dutch families maps a locus for abdominal aortic aneurysms to chromosome 19q13.3.

OBJECTIVES: Elucidation of the genetic background of familial abdominal aortic aneurysm (AAA) suggests a genetic etiology. METHODS AND RESULTS: We carried out a genome-wide scan in three Dutch families with four or five affected siblings. Suggestive loci were further studied by subsequent fine mapping of the locus performed in 101 affected sib-pairs. The genome-wide scan was performed with 400 DNA markers and results were given as non-parametric, multipoint linkage scores (NPL). We observed a suggestive linkage for AAA (NPL score 3.25 at D19S902, 72.72 cM) on chromosome 19q in the three families. After fine mapping on chromosome 19, the NPL score became nominal in the 101 affected sib-pairs. A separate analysis of the three families with fine mapping revealed a peak with significant evidence for linkage (NPL score 3.95 at D19S904, 78.08 cM) on chromosome 19q. This peak was situated to the right compared to the region found in a previously published article for familial AAA on chromosome 19q. CONCLUSIONS: Our results identified a candidate locus in three Dutch families with AAA at chromosome 19q13.3. Separate analysis of these three families provides evidence for genetic heterogeneity.     

Genome-wide scan for type 1 diabetic nephropathy in the Finnish population reveals suggestive linkage to a single locus on chromosome 3q

Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 as well as type 2 diabetes, and accounts for 40% of end-stage renal disease in the Western world. Familial clustering of DN suggests importance of genetic factors in the development of the disease. In the present study, we performed a two-stage genome-wide scan to search for chromosomal loci containing susceptibility genes for nephropathy in patients with type 1 diabetes. In total, 83 discordant sib pairs (DSPs), sibs concordant for type 1 diabetes but discordant for nephropathy, were collected from Finland, a homogeneous population with one of the highest incidences of type 1 diabetes. To map loci for DN, we applied DSP analysis to detect linkage. In the initial scan, 73 DSPs were typed using 900 markers with an average intermarker distance of approximately 4 cM. Multipoint DSP analysis identified five chromosome regions (3q, 4p, 9q, 16q, and 22p) with maximum logarithm of odds (LOD) score (MLS) >or=1.0 (corresponding to a nominal P-value 相似文献   

Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q.

Macrovascular disease is a major complication of type 2 diabetes. Epidemiological data suggest that the risk of macrovascular complications may predate the onset of hyperglycemia. Hypertriglyceridemia, low levels of HDL cholesterol, and an atherogenic profile characterize the insulin resistance/metabolic syndrome that is also prevalent among nondiabetic members of familial type 2 diabetic kindreds. To identify the genes for lipid-related traits, we first performed a 10-cM genome scan using 440 markers in 379 members of 19 multiplex families ascertained for two diabetic siblings (screening study). We then extended findings for three regions with initial logarithm of odds (LOD) scores >1.5 to an additional 23 families, for a total of 576 genotyped individuals (extended study). We found heritabilities for all lipid measures in the range of 0.31 to 0.52, similar to those reported by others in unselected families. However, we found the strongest evidence for linkage of triglyceride levels to chromosome 19q13.2, very close to the ApoC2/ApoE/ApoC1/ApoC4 gene cluster (LOD 2.56) in the screening study; the LOD increased to 3.16 in the extended study. Triglyceride-to-HDL cholesterol ratios showed slightly lower LOD scores (2.73, extended family) in this same location. Other regions with LOD scores >2.0 included HDL linkage to chromosome 1q21-q23, where susceptibility loci for both familial type 2 diabetes and familial combined hyperlipidemia have been mapped, and to chromosome 2q in the region of the NIDDM1 locus. Neither region showed stronger evidence for linkage in the extended studies, however. Our results suggest that genes in or near the ApoE/ApoC2/ApoC1/ApoC4 cluster on 19q13.2 may contribute to the commonly observed hypertriglyceridemia and low HDL seen in diabetic family members and their offspring, and thus may be a candidate locus for the insulin resistance syndrome.     

A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.     

Quantitative trait loci on chromosome 8q24 for pancreatic beta-cell function and 7q11 for insulin sensitivity in obese nondiabetic white and black families: evidence from genome-wide linkage scans in the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study

Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic beta-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid-lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For beta-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes-associated traits.     

A genome-wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County, Texas

We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions.     

A genomewide linkage scan for abdominal subcutaneous and visceral fat in black and white families: The HERITAGE Family Study

Abdominal visceral fat (AVF), abdominal subcutaneous fat (ASF), and abdominal total fat (ATF) were measured using a computed tomography scan, both before (baseline) and after (post) a 20-week endurance exercise training protocol in the HERITAGE Family Study. Each of the baseline and response (post minus baseline) measures was adjusted for several covariates, including total fat mass, and responses to training were further adjusted for baseline levels. Multipoint variance components linkage analysis using a genomewide scan of 344 markers was conducted separately by race using race-specific allele frequencies. Several promising results (P < 0.0023) were obtained. For baseline AVF, the best evidence was on 2q22.1 and 2q33.2-q36.3 (including the IRS1 locus) in whites, with suggestive findings on 7q22.2-q31.3 (including the LEP locus) in blacks. Although several regions were indicated for baseline ASF, only 4q31.22-q32.2 and 11p15.4-p11.2 replicated the results of another study. For responses to training, promising results were limited to ASF and ATF primarily on 7q36.2 (including NOS3) in blacks, with suggestive regions (P < 0.01) on 1q21.2-q24.1 (S100A, ATP1A2, and ATP1B1), 10q25.2 (ADRA2A), and 11p15.5 (IGF2). In summary, the 4q and 11p regions have now been implicated in two independent studies for ASF; further research is warranted to identify the genes and mutations in these regions that are responsible for fat accumulation in the abdominal depot. Additional work in an independent sample is needed to verify the linkages for baseline AVF as well as the response measures.