ADHD in Dutch adults: Heritability and linkage study

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental phenotype that persists into adulthood. This study investigated the heritability of inattentive and hyperactive symptoms and of total ADHD symptomatology load (ADHD index) in adults and performed linkage scans for these dimensions. Data on sibling pairs and their family members from the Netherlands Twin Register with genotype and phenotype data for inattention, hyperactivity and ADHD index (～750 sib‐pairs) were analyzed. Phenotypes were assessed with the short self‐report form of the Conners' Adult ADHD Rating Scales (CAARS). Heritabilities were estimated in SOLAR under polygenic models. Genome‐wide linkage scans were performed using variance components (VC) in MERLIN and MINX and model‐based linkage analysis was carried out in MENDEL with empirical evaluation of the results via simulations. Heritability estimates for inattention, hyperactivity and ADHD index were 35%, 23%, and 31%, respectively. Chromosomes 18q21.31–18q21.32 (VC LOD = 4.58, p_emp = 0.0026) and 2p25.1 (LOD = 3.58, p_emp = 0.0372) provided significant evidence for linkage for inattention and the ADHD index, respectively. The QTL on chromosome 2p25.1 also showed suggestive linkage for hyperactivity. Two additional suggestive QTLs for hyperactivity and the ADHD index shared the same location on chromosome 3p24.3–3p24.1. Finally, a suggestive QTL on 8p23.3–8p23.2 for hyperactivity was also found. Heritability of inattention, hyperactivity and total ADHD symptoms is lower in adults than in children. Chromosomes 18q and 2p are likely to harbor genes that influence several aspects of adult ADHD. © 2011 Wiley‐Liss, Inc.     

Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions

Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10⁻⁰⁶, KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.     

Genomewide Linkage Scan for Combined Obesity Phenotypes using Principal Component Analysis

Traditional whole genome linkage scans for obesity were usually performed for a number of correlated obesity related phenotypes separately without considering their correlations. The purpose of this study was to identify quantitative trait loci (QTLs) underlying variations in multiple correlated obesity phenotypes. We performed principal component analysis (PCA) for four highly correlated obesity phenotypes (body mass index [BMI], fat mass, percentage of fat mass [PFM], and lean mass) in a sample of 427 pedigrees (comprising 3,273 individuals) and generated two independent principal components (PC1 and PC2). A whole genome linkage scan (WGS) was then conducted for PC1 and PC2. For PC1, the strongest linkage signal was identified on chromosome 20p12 (LOD = 2.67). For PC2, two suggestive linkages were found on 5q35 (LOD = 2.03) and 7p22 (LOD = 2.18). This study provided evidence supporting several previously identified linkage regions for obesity (e.g., 1p36, 6p23 and 7q34). In addition, our approach by linear combination of highly correlated obesity phenotypes identified several novel QTLs which were not found in genome linkage scans for individual phenotypes.     

Identification of QTLs for serum lipid levels in a female sib-pair cohort: a novel application to improve the power of two-locus linkage analysis

Using a novel approach for a two-locus model that provides a greatly increased power to detect multiple quantitative trait loci (QTLs) in simulated data, we identified in a sample of 961 female sib-pairs, three genome-wide significant QTLs for apolipoprotein A1 on chromosomes 8p21.1-q13.1 (LOD score 3.71), 9q21.32-33.1 (LOD score 3.28) and 10p15.1-p13 (LOD score 5.51), two for lipoprotein (a) on chromosomes 6q25.2-q27 (LOD score 10.18) and 21q21.1-q21.3 (LOD score 4.57) and two for triglycerides on chromosomes 4q28.3-32.1 (LOD score 3.71) and 5q23.1-q32 (LOD score 3.60). The two-locus ordered-subset analysis has led to the confirmation of known and likely identification of novel regions linked to serum lipid levels that would have otherwise been missed and deserves wider application in linkage analyses of quantitative traits. Given the relative lack of power for the sample sizes commonly used in human genetics linkage studies, minor QTL effects often go undetected and those that are detected will be upwardly biased. We show through simulation that the discrepancy between the real and estimated QTL-effects is often likely to generate an unpredictable source of false-negative errors, using multi-locus models, reducing the power to detect multiple QTLs through oligogenic linkage analysis. The successful simultaneous modelling of the identified QTLs in a multi-locus context helps to eliminate false positives and increases the power to detect linkages, adding compelling evidence that they are likely to be reliable QTLs for these lipid traits.     

Genome-wide search for nevus density shows linkage to two melanoma loci on chromosome 9 and identifies a new QTL on 5q31 in an adult twin cohort

The density of acquired melanocytic nevi represents an important risk factor for malignant melanoma. Total body nevus counts were collected in a cross-sectional study of 1730 healthy females from the UK Adult twin registry comprising 709 dizygous and 156 monozygous pairs. Nevus density (ND) increased up to the age of 35 years and then gradually declined. Quantitative genetic analysis showed a smaller genetic influence (36%) on ND up to 35 years, compared with after 35 years where it rose to 59%. Using a sub-sample of 1238 genotyped individuals, we performed distinct genome-wide scans for individuals above and below 35 separately. In the younger sub-sample, we confirmed a quantitative trait locus (QTL) for ND on chromosomes 9p21 (LOD=2.54), a region already linked to both familial melanoma and ND. We also observed a linkage signal on 9q21 (LOD=2.55) overlapping a recently reported susceptibility locus for ocular and cutaneous melanoma in Danish families. The strongest evidence of linkage identified a novel QTL on chromosome 5q31-32 (LOD=3.47). None of these linkages was observed in the group aged 35 years and over, which showed suggestive linkage on chromosome 2p24 (LOD=2.75). To the best of our knowledge, this is the first genome-wide search for ND in a large sample of healthy adults. The results suggest that different sets of genes are likely to influence the processes leading to the appearance of nevi and their involution. They provide both novel and replicated QTLs for nevus development, some of which might overlap with those for melanoma and warrant detailed investigation.     

Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.     

Serum Lipids in the GENECARD Study of Coronary Artery Disease Identify Quantitative Trait Loci and Phenotypic Subsets on Chromosomes 3q and 5q

Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results.
We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06).
Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.     

A meta-analysis of four European genome screens (GIFT Consortium) shows evidence for a novel region on chromosome 17p11.2-q22 linked to type 2 diabetes

Positional cloning is expected to identify novel susceptibility genes underlying complex traits, but replication of genome-wide linkage scan findings has proven erratic. To improve our ability to detect and prioritize chromosomal regions containing type 2 diabetes susceptibility genes, the GIFT consortium has implemented a meta-analysis of four scans conducted in European samples. These included the Botnia I and Botnia II scans, with respectively 58 and 353 pedigrees from Finland and Sweden, the Warren 2 scan performed in 573 multiplex sibships from the UK, and a scan of 143 families from France. The meta-analysis was implemented using the genome-search analysis method (GSMA), an exploratory data analysis technique which is robust across study designs. The analysis provided evidence for linkage of type 2 diabetes to six regions, with the strongest evidence on chromosome 17p11.2-q22 (P=0.0016), followed by 2p22.1-p13.2 (P=0.027), 1p13.1-q22 (P=0.028), 12q21.1-q24.12 (P=0.029), 6q21-q24.1 (P=0.033) and 16p12.3-q11.2 (P=0.033). Linkage analysis of the pooled raw genotype data generated maximum LOD scores in the same regions as identified by GSMA. Altogether, our results have indicated that GSMA is a valuable tool to identify chromosomal regions of interest and that accumulating evidence for linkage from small peaks detected across several samples may be more important than getting a high peak in a single sample. This meta-analysis has led to identification of a novel region on chromosome 17 linked to type 2 diabetes; this region has not been highlighted in any published scan to date but on the basis of these data justifies further exploration.     

A male-specific quantitative trait locus on 1p21 controlling human stature

Background: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. Objective: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. Methods: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. Results: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. Conclusions: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.     

Meta-analysis of genome-wide linkage studies for quantitative lipid traits in African Americans

Genetic influences on lipid traits have been suggested by numerous studies. In addition to heritability studies, over 50 genome scans have been performed to identify regions of linkage for quantitative lipid levels. Five of these scans have been performed in African Americans (four univariate and one bivariate linkage analysis), but with results that have been largely inconclusive. Linkage analyses are often limited by both sample size and heterogeneity, which may lead to nominal LOD scores or lack of evidence for linkage; the use of meta-analysis to combine linkage results from populations with similar ethnic backgrounds may help overcome some of these limitations. Thus, we performed a meta-analysis using data from four genome scans conducted in African American families to identify chromosomal regions showing evidence of linkage for total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL) and high density lipoprotein cholesterol (HDL). Significant evidence (i.e. P<0.00042) for linkage was found for LDL on chromosome 1q32.1-q41 (Pweighted=0.00014 and Punweighted=0.00007) and 1q41-q44 (Pweighted=0.00017 and Punweighted=0.00014). We found suggestive evidence (i.e. P<0.00847) for TG on 16p12.1-q11.2 and for HDL on 4p15.1-p11. We also assessed heterogeneity between studies and found significant evidence for low heterogeneity for both regions on chromosome 1q (P=0.0300 and P=0.0279, respectively) for LDL and chromosome 16 (P=0.0429) for TG. Statistically significant evidence for linkage and low heterogeneity on chromosome 1q therefore suggest that this region may harbor a gene underlying the inheritance of LDL in African Americans.     

Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population

The genetic basis of cardiovascular disease (CVD) with its complex etiology is still largely elusive. Plasma levels of lipids and apolipoproteins are among the major quantitative risk factors for CVD and are well-established intermediate traits that may be more accessible to genetic dissection than clinical CVD end points. Chromosome 19 harbors multiple genes that have been suggested to play a role in lipid metabolism and previous studies indicated the presence of a quantitative trait locus (QTL) for cholesterol levels in genetic isolates. To establish the relevance of genetic variation at chromosome 19 for plasma levels of lipids and apolipoproteins in the general, out-bred Caucasian population, we performed a linkage study in four independent samples, including adolescent Dutch twins and adult Dutch, Swedish and Australian twins totaling 493 dizygotic twin pairs. The average spacing of short-tandem-repeat markers was 6-8 cM. In the three adult twin samples, we found consistent evidence for linkage of chromosome 19 with LDL cholesterol levels (maximum LOD scores of 4.5, 1.7 and 2.1 in the Dutch, Swedish and Australian sample, respectively); no indication for linkage was observed in the adolescent Dutch twin sample. The QTL effects in the three adult samples were not significantly different and a simultaneous analysis of the samples increased the maximum LOD score to 5.7 at 60 cM pter. Bivariate analyses indicated that the putative LDL-C QTL also contributed to the variance in ApoB levels, consistent with the high genetic correlation between these phenotypes. Our study provides strong evidence for the presence of a QTL on chromosome 19 with a major effect on LDL-C plasma levels in outbred Caucasian populations.     

A genome-wide linkage scan for iron phenotype quantitative trait loci: the HEIRS Family Study

Iron overload phenotypes in persons with and without hemochromatosis are variable. To investigate this further, probands with hemochromatosis or evidence of elevated iron stores and their family members were recruited for a genome-wide linkage scan to identify potential quantitative trait loci (QTL) that contribute to variation in transferrin saturation (TS), unsaturated iron-binding capacity (UIBC), and serum ferritin (SF). Genotyping utilized 402 microsatellite markers with average spacing of 9 cM. A total of 943 individuals, 64% Caucasian, were evaluated from 174 families. After adjusting for age, gender, and race/ethnicity, there was evidence for linkage of UIBC to chromosome 4q logarithm of the odds (LOD) = 2.08, p = 0.001) and of UIBC (LOD = 9.52), TS (LOD = 4.78), and SF (LOD = 2.75) to the chromosome 6p region containing HFE (each p < 0.0001). After adjustments for HFE genotype and other covariates, there was evidence of linkage of SF to chromosome 16p (LOD = 2.63, p = 0.0007) and of UIBC to chromosome 5q (LOD = 2.12, p = 0.002) and to chromosome 17q (LOD = 2.19, p = 0.002). We conclude that these regions should be considered for fine mapping studies to identify QTL that contribute to variation in SF and UIBC.     

Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels

Autosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL-cholesterol (LDL-C) levels below the 50th percentile for age and gender prior to lipid-lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss-of-function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL-C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholesterolemic phenotype were not found. The common variants p.N902N, c.3842+82T>A, p.D2312D, and p.E4181K in APOB, and c.1863+94A>G in PCSK9 were significantly more prevalent in our cohort compared to the general European population. Interestingly, 40% of our probands carried at least one minor allele for all four common APOB variants compared to 1.5% in the general European population. While we found a low prevalence of rare variants in our cohort, our data suggest that regions in proximity of the analyzed loci, and linked to specific common haplotypes, might harbor additional variants that correct an ADH phenotype.     

Genome-wide linkage analysis for circulating levels of adipokines and C-reactive protein in the Quebec family study (QFS)

Adipose tissue synthesizes and secretes a wide range of biologically active molecules considered as inflammatory markers whose dysregulation in obesity plays a role in the development of insulin resistance and vascular disorders. Thus, finding genes that influence circulating levels of inflammatory biomarkers may provide insights into the genetic determinants of obesity-related metabolic diseases. We performed linkage analyses for fasting plasma levels of adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor-necrosis factor-alpha (TNF-alpha) in 764 subjects enrolled in the Quebec family study (QFS). A maximum of 393 pairs of siblings from 211 nuclear families were available for analyses. A total of 443 markers spanning the 22 autosomal chromosomes with an average inter-marker distance of 6.24 Mb were genotyped. Linkage was tested using both allele-sharing (SIBPAL) and variance component linkage methods (MERLIN). We showed suggestive evidence of linkage for plasma adiponectin levels on chromosome 15q21.1 [D15S659; logarithm of the odds (LOD) score = 2.23], 3q13.33 (D3S3023; LOD = 2.09), 20q13.2 (D20S197; LOD = 1.96) and 14q32.2 (D14S1426; LOD = 1.79). Evidence of linkage (SIBPAL) was also found for CRP on 12p11.23 (P = 0.001) and 12q15 (P = 0.0005) and for IL-6 on 14q12 (P = 0.002). None of these linkages remained significant after adjustment for body mass index. No evidence of linkage was found for TNF-alpha plasma levels. These results suggest that several QTLs can influence plasma levels of adiponectin and CRP, partly via their effects on adiposity.     

Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q

Platelet count is a highly heritable trait with genetic factors responsible for around 80% of the phenotypic variance. We measured platelet count longitudinally in 327 monozygotic and 418 dizygotic twin pairs at 12, 14 and 16 years of age. We also performed a genome-wide linkage scan of these twins and their families in an attempt to localize QTLs that influenced variation in platelet concentrations. Suggestive linkage was observed on chromosome 19q13.13-19q13.31 at 12 (LOD = 2.12, P = 0.0009), 14 (LOD = 2.23, P = 0.0007) and 16 (LOD = 1.01, P = 0.016) years of age and multivariate analysis of counts at all three ages increased the LOD to 2.59 (P = 0.0003). A possible candidate in this region is the gene for glycoprotein VI, a receptor involved in platelet aggregation. Smaller linkage peaks were also seen at 2p, 5p, 5q, 10p and 15q. There was little evidence for linkage to the chromosomal regions containing the genes for thrombopoietin (3q27) and the thrombopoietin receptor (1q34), suggesting that polymorphisms in these genes do not contribute substantially to variation in platelet count between healthy individuals.     

Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin

Serotonin has been implicated in common disorders involving the central nervous, gastrointestinal, cardiovascular, and pulmonary systems. We describe the first genome-wide screen to identify quantitative trait loci (QTLs) influencing whole blood serotonin in 567 members of a single large pedigree, using a novel association-based mapping approach. We identified an association between the beta3 integrin (ITGB3) Leu33Pro polymorphism on 17q21 and whole blood serotonin levels (P-value = 9.8 x 10(-5)). This variant explained the evidence for linkage in this region when included as a covariate in the linkage analysis (change in LOD from 1.87 to 0.16), indicating that ITGB3 may be an important serotonin QTL.     

A Whole Genome Linkage Scan Identifies Multiple Chromosomal Regions Influencing Adiposity‐Related Traits among Samoans

We conducted a genome‐wide scan in 46 pedigrees, with 671 phenotyped adults, from the independent nation of Samoa to map quantitative trait loci (QTLs) for adiposity‐related phenotypes, including body mass index (BMI), abdominal circumference (ABDCIR), percent body fat (%BFAT), and fasting serum leptin and adiponectin. A set of 378 autosomal and 14 X chromosomal microsatellite markers were genotyped in 572 of the adults. Significant genetic correlations (0.82–0.96) were detected between pairs of BMI, ABDCIR, %BFAT and leptin. Suggestive linkages were found on 13q31 (LOD = 2.30 for leptin, LOD = 2.48 for %BFAT, LOD = 2.04 for ABDCIR, and LOD = 2.09 for BMI) and on 9p22 (LOD = 3.08 for ABDCIR and LOD = 2.53 for %BFAT). Furthermore, bivariate linkage analyses indicated that the genetic regions on 9p22 (bivariate LOD 2.35–3.10, LOD_eq (1df) 1.88–2.59) and 13q31 (bivariate LOD 1.96–2.64, LOD_eq 1.52–2.21) might harbor common major genes with pleiotropic effects. Other regions showing suggestive linkage included 4q22 (LOD = 2.95) and 7p14 (LOD = 2.64) for %BFAT, 2q13 for adiponectin (LOD = 2.05) and 19q12 for BMI‐adjusted leptin (LOD = 2.03). Further fine mapping of these regions may help identify the genetic variants contributing to the development of obesity in Samoan adults.     

Combined analysis of genomewide scans for adult height: results from the NHLBI Family Blood Pressure Program

A combined analysis of genome scans was performed for adult height in the NHLBI Family Blood Pressure Program. Height data were available on 6752 individuals. Linkage analysis was performed first separately for each of the eight ethnic groups in the four networks using the variance component method. To increase the power to detect the common genetic components affecting height for all the individuals, a linkage analysis was performed subsequently for the combined data set by pooling the average allele-sharing IBD () for all groups. By combining the data, we replicated evidence for a QTL influencing adult height on chromosome 7 (7q31) (LOD=2.46), which has been reported in two previous studies. Suggestive linkage (LOD>1) was found in another six regions in our combined analysis. Evidence for linkage for two of these regions (2p12, 20p11) has also been reported previously.     

Several genomic regions potentially containing QTLs for bone size variation were identified in a whole-genome linkage scan

Bone size is an important determinant of osteoporotic fractures. For a sample of 53 pedigrees that contains more than 10,000 relative pairs informative for linkage analyses, we performed a whole-genome linkage scan using 380 microsatellite markers to identify genomic regions that may contain QTLs of bone size (two dimensional measurement by dual energy X-ray absorptiometry). We conducted two- and multi-point linkage analyses. Several potentially important genomic regions were identified. For example, the genomic region 17q23 may contain a QTL for wrist (ultra distal) bone size variation; a LOD score of 3.98 is achieved at D17S787 in two-point analyses and a maximum LOD score (MLS) of 3.01 is achieved in multi-point analyses in 17q23. 19p13 may contain a QTL for hip bone size variation; a LOD score of 1.99 is achieved at D19S226 in two-point analyses and a MLS of 2.83 is achieved in 19p13 in multi-point analyses. The genomic region identified on chromosome 17 for wrist bone size seems to be consistent with that identified for femur head width variation in an earlier whole-genome scan study. The genomic regions identified in this study and an earlier investigation on one-dimensional bone size measurement by radiography are compared. The two studies may form a basis for further exploration with larger samples and/or denser markers for confirmation and fine mapping studies to eventually identify major functional genes and the associated etiology for osteoporosis.     

Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men < or =50 years) and two suggestive QTL for LS-BMD on chromosomes 18p11 (LOD score +2.83; women >50 years) and 20q13 (LOD score +3.20; women < or =50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.