The Human Obesity Gene Map: The 1996 Update

An update of the human obesity gene map up to October 1996 is presented. Evidence from Mendelian disorders exhibiting obesity as a clinical feature, single-gene mutation rodent models, quantitative trait loci uncovered in crossbreeding experiments with mouse, rat, and pig models, association and case-control studies with candidate genes, and linkage studies with genes and other markers is reviewed. All chromosomal locations of the animal loci are converted into human genome locations based on syntenic relationships between the genomes. A complete listing of all these loci reveals that only 4 of the 24 human chromosomes are not yet represented, i.e., 9, 18, 21, and Y. Several chromosome arms are characterized by the presence of several putative loci. The following arms include at least three such loci: 1p, 1q, 3p, 4q, 6p, 7q, 8p, 8q, 11p, 11q, 15q, 20q, and Xq. Studies with negative association and linkage results are also reviewed.     

The Human Obesity Gene Map: The 1998 Update

PÉRUSSE, LOUIS, YVON C. CHAGNON, JOHN WEISNAGEL, AND CLAUDE BOUCHARD. The human obesity gene map: the 1998 update. Obes Res. 1999;7:111–129. An update of the human obesity gene map incorporating published results up to the end of October 1998 is presented. Evidence from the human obesity cases caused by single gene mutations; other Mendelian disorders exhibiting obesity as a clinical feature; quantitative trait loci uncovered in human genome-wide scans and in crossbreeding experiments with mouse, rat, and pig models; association and case-control studies with candidate genes; and linkage studies with genes and other markers is reviewed. The most noticeable changes from the 1997 update is the number of obesity cases due to single gene mutations that increased from three cases due to mutations in two genes to 25 cases due to 12 mutations in seven genes. A look at the obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity-related phenotypes are found on all but chromosome Y of the human chromosomes. Some chromosomes show at least three putative loci related to obesity on both arms (1, 2, 3, 6, 7, 8, 9, 11, 17, 19, 20, and X) and several on one chromosome arm only (4q, 5q, 10q, 12q, 13q, 15q, 16p, and 22q). The number of genes and other markers that have been associated or linked with human obesity phenotypes is increasing very rapidly and now approaches 27.     

The Human Obesity Gene Map: The 2001 Update

This report constitutes the eighth update of the human obesity gene map, incorporating published results up to the end of October 2001. Evidence from the rodent and human obesity cases caused by single-gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) uncovered in human genome-wide scans and in crossbreeding experiments in various animal models, association and linkage studies with candidate genes and other markers is reviewed. The human cases of obesity related in some way to single-gene mutations in six different genes are incorporated. Twenty-five Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models currently reaches 165. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 174 studies reporting positive associations with 58 candidate genes. Finally, 59 loci have been linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity-related phenotypes can be found on all chromosomes except chromosome Y. A total of 54 new loci have been added to the map in the past 12 months, and the number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes is now above 250. Likewise, the number of negative studies, which are only partially reviewed here, is also on the rise.     

The Human Obesity Gene Map: The 2000 Update

This report constitutes the seventh update of the human obesity gene map incorporating published results up to the end of October 2000. Evidence from the rodent and human obesity cases caused by single‐gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci uncovered in human genome‐wide scans and in cross‐breeding experiments in various animal models, and association and linkage studies with candidate genes and other markers are reviewed. Forty‐seven human cases of obesity caused by single‐gene mutations in six different genes have been reported in the literature to date. Twenty‐four Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different quantitative trait loci reported from animal models currently reaches 115. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 130 studies reporting positive associations with 48 candidate genes. Finally, 59 loci have been linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map reveals that putative loci affecting obesity‐related phenotypes can be found on all chromosomes except chromosome Y. A total of 54 new loci have been added to the map in the past 12 months and the number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes is now above 250. Likewise, the number of negative studies, which are only partially reviewed here, is also on the rise.     

The Human Obesity Gene Map: The 2002 Update

This is the ninth update of the human obesity gene map, incorporating published results through October 2002 and continuing the previous format. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome‐wide scans and various animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. For the first time, transgenic and knockout murine models exhibiting obesity as a phenotype are incorporated (N = 38). As of October 2002, 33 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and the causal genes or strong candidates have been identified for 23 of these syndromes. QTLs reported from animal models currently number 168; there are 68 human QTLs for obesity phenotypes from genome‐wide scans. Additionally, significant linkage peaks with candidate genes have been identified in targeted studies. Seven genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 222 studies reporting positive associations with 71 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. More than 300 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http:obesitygene.pbrc.edu .     

The Human Obesity Gene Map: The 2003 Update

This is the tenth update of the human obesity gene map, incorporating published results up to the end of October 2003 and continuing the previous format. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome‐wide scans and animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. Transgenic and knockout murine models relevant to obesity are also incorporated (N = 55). As of October 2003, 41 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. QTLs reported from animal models currently number 183. There are 208 human QTLs for obesity phenotypes from genome‐wide scans and candidate regions in targeted studies. A total of 35 genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 272 studies reporting positive associations with 90 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, more than 430 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http:obesitygene.pbrc.edu .     

The Human Obesity Gene Map: The 2004 Update

This paper presents the eleventh update of the human obesity gene map, which incorporates published results up to the end of October 2004. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTLs) from animal cross‐breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2004, 173 human obesity cases due to single‐gene mutations in 10 different genes have been reported, and 49 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 166 genes which, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 221. The number of human obesity QTLs derived from genome scans continues to grow, and we have now 204 QTLs for obesity‐related phenotypes from 50 genome‐wide scans. A total of 38 genomic regions harbor QTLs replicated among two to four studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably with 358 findings of positive associations with 113 candidate genes. Among them, 18 genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, >600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful publications and genomic and other relevant sites can be found at http:obesitygene.pbrc.edu .     

The human obesity gene map: the 2005 update

This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.     

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.     

Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis

To date, several susceptibility loci for systemic lupus erythematosus (SLE) have been identified by individual genome-wide scans, but many of these loci have shown inconsistent results across studies. Additionally, many individual studies are at the lower limit of acceptable power recommended for declaring significant linkage. The genome search meta-analysis (GSMA) has been proposed as a valid and robust method for combining several genome scan results. The aim of this study is to investigate whether there is any consistent evidence of linkage across multiple studies, and to identify novel SLE susceptibility loci by using GSMA method. Twelve genome scan results generated from nine independent studies have been used for the present GSMA. All together, the data consists of 605 families with 1,355 SLE affected individuals from three self-reported ethnicities; Caucasian, African-American, and Hispanic. For each study, the genome was divided into 120 bins (30 cM) and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies following which the significance was assessed by the permutation tests. The present study identified two genomic locations at 6p22.3–6p21.1 and 16p12.3–16q12.2 that met genome-wide significance (p<0.000417). The identified region at 6p22.3–6p21.1 contains the HLA region. The combined p-values using Fisher’s method also supported the significance in these regions. Clustering of significant adjacent bins was observed for chromosomes 6 and 16. Additionally, there are 12 other bins with two point-wise p-values (Psumrnk and Pord) <0.05, suggesting that these bin regions are highly likely to contain SLE susceptibility loci. Among them, present GSMA also identified two novel regions at 4q32.1–4q34.3 and 13q13.2–13q22.2. However, separate analysis using only Caucasian populations identified the strongest evidence for linkage at chromosome 6p21.1–6q15 (Psumrnk=0.00021). One interesting novel region suggests that 3q22.1–3q25.33 (Psumrnk=0.01376) may be an ethnicity-specific SLE linkage. In summary, the present GSMA have identified two statistically significant genomic regions that reconfirmed the SLE linkage at chromosomes 6 and 16.     

Genome-Wide Linkage Scan Identifies Two Novel Genetic Loci for Coronary Artery Disease: In GeneQuest Families

Coronary artery disease (CAD) is the leading cause of death worldwide. Recent genome-wide association studies (GWAS) identified >50 common variants associated with CAD or its complication myocardial infarction (MI), but collectively they account for <20% of heritability, generating a phenomena of “missing heritability”. Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL) analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL  = 5.49) and 3q29 (NPL  = 6.84). We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL  = 3.18–4.07). These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD.     

Fine mapping and SNP analysis of positional candidates at the preeclampsia susceptibility locus (PREG1) on chromosome 2

Genome scans in Icelandic, Australian and New Zealand, and Finnish families have localized putative susceptibility loci for preeclampsia/ eclampsia to chromosome 2. The locus mapped in the Australian and New Zealand study (designated PREG1) was thought to be the same locus as that identified in the Icelandic study. In both these studies, two distinct quantitative trait locus (QTL) regions were evident on chromosome 2. Here, we describe our fine mapping of the PREG1 locus and a genetic analysis of two positional candidate genes. Twenty-five additional microsatellite markers were genotyped within the 74-cM linkage region defined by the combined Icelandic and Australian and New Zealand genome scans. The overall position and shape of the localization evidence obtained using nonparametric multipoint analysis did not change from that seen previously in our 10-cM resolution genome scan; two peaks were displayed, one on chromosome 2p at marker D2S388 (107.46 cM) and the other on chromosome 2q at 151.5 cM at marker D2S2313. Using the robust two-point linkage analysis implemented in the Analyze program, all 25 markers gave positive LOD scores with significant evidence of linkage being seen at marker D2S2313 (151.5 cM), achieving a LOD score of 3.37 under a strict diagnostic model. Suggestive evidence of linkage was seen at marker D2S388 (107.46 cM) with a LOD score of 2.22 under the general diagnostic model. Two candidate genes beneath the peak on chromosome 2p were selected for further analysis using public single nucleotide polymorphisms (SNPs) within these genes. Maximum LOD scores were obtained for an SNP in TACR1 (LOD = 3.5) and for an SNP in TCF7L1 (LOD = 3.33), both achieving genome-wide significance. However, no evidence of association was seen with any of the markers tested. These data strongly support the presence of a susceptibility gene on chromosome 2p11-12 and substantiate the possibility of a second locus on chromosome 2q23.     

A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND)

Objective

Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.

Methods

Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.

Results

The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10⁻⁵) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10⁻⁴) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10⁻⁴) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.

Conclusion

The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.     

Current Status of the Human Obesity Gene Map

An overview of the status of the human obesity gene map up to October 1995 is presented. The evidence is drawn from several lines of clinical and experimental research. First, 12 loci linked to Mendelian disorders exhibiting obesity as one clinical feature are reviewed. Second, six loci causing obesity in rodent models of the disease are considered. Third, eight chromosomal regions where quantitative trait loci, identified by crossbreeding experiments with informative strains of mice, are defined. Fourth, 10 candidate genes exhibiting a statistical association with BMI or body fat are introduced. Fifth, nine loci found to be linked to a relevant phenotype are listed and the four cases for which the evidence for linkage is strongest are emphasized. The latter are mapped to 2p25, 6p21.3, 7q33 and 20q12-13.11. Finally, the studies that have concluded that there was no association or linkage with a marker or gene are also reviewed. It is recommended that a system be developed by the obesity research community to ensure that an accurate and easily accessible computerized version of the human obesity gene map becomes available in the near future.     

A genome-wide linkage scan identifies multiple chromosomal regions influencing serum lipid levels in the population on the Samoan islands

Abnormal lipid levels are important risk factors for cardiovascular diseases. We conducted genome-wide variance component linkage analyses to search for loci influencing total cholesterol (TC), LDL, HDL and triglyceride in families residing in American Samoa and Samoa as well as in a combined sample from the two polities. We adjusted the traits for a number of environmental covariates, such as smoking, alcohol consumption, physical activity, and material lifestyle. We found suggestive univariate linkage with log of the odds (LOD) scores > 3 for LDL on 6p21-p12 (LOD 3.13) in Samoa and on 12q21-q23 (LOD 3.07) in American Samoa. Furthermore, in American Samoa on 12q21, we detected genome-wide linkage (LOD(eq) 3.38) to the bivariate trait TC-LDL. Telomeric of this region, on 12q24, we found suggestive bivariate linkage to TC-HDL (LOD(eq) 3.22) in the combined study sample. In addition, we detected suggestive univariate linkage (LOD 1.9-2.93) on chromosomes 4p-q, 6p, 7q, 9q, 11q, 12q 13q, 15q, 16p, 18q, 19p, 19q and Xq23 and suggestive bivariate linkage (LOD(eq) 2.05-2.62) on chromosomes 6p, 7q, 12p, 12q, and 19p-q. In conclusion, chromosome 6p and 12q may host promising susceptibility loci influencing lipid levels; however, the low degree of overlap between the three study samples strongly encourages further studies of the lipid-related traits.     

Structural Chromosome Abnormalities Associated with Obesity: Report of Four New subjects and Review of Literature

Obesity in humans is a complex polygenic trait with high inter-individual heritability estimated at 40-70%. Candidate gene, DNA linkage and genome-wide association studies (GWAS) have allowed for the identification of a large set of genes and genomic regions associated with obesity. Structural chromosome abnormalities usually result in congenital anomalies, growth retardation and developmental delay. Occasionally, they are associated with hyperphagia and obesity rather than growth delay. We report four new individuals with structural chromosome abnormalities involving 10q22.3-23.2, 16p11.2 and Xq27.1-q28 chromosomal regions with early childhood obesity and developmental delay. We also searched and summarized the literature for structural chromosome abnormalities reported in association with childhood obesity.     

Isolation and analysis of DNA markers specific to human chromosome 15.

Chromosome-specific DNA markers provide a powerful approach for studying complex problems in human genetics and offer an opportunity to begin understanding the human genome at the molecular level. The approach described here for isolating and characterizing DNA markers specific to human chromosome 15 involved construction of a partial chromosome-15 phage library from a human/Chinese hamster cell hybrid with a single human chromosome 15. Restriction fragments that identified unique- and low-copy loci on chromosome 15 were isolated from the phage inserts. These fragments were regionally mapped to the chromosome by three methods, including Southern analysis with a mapping panel of cell hybrids, in situ hybridization to metaphase chromosomes, and quantitative hybridization or dosage analysis. A total of 42 restriction fragments of unique- and low-copy sequences were identified in 14 phage. The majority of the fragments that have been characterized so far exhibited the hybridization pattern of a unique locus on chromosome 15. Regional mapping assigned these markers to specific locations on chromosome 15, including q24-25, q21-23, q13-14, q11-12, and q11. RFLP analysis revealed that several markers displayed polymorphisms at frequencies useful for genetic linkage analysis. The markers mapped to the proximal long arm of chromosome 15 are particularly valuable for the molecular analysis of Prader-Willi syndrome, which maps to this region. Polymorphic markers in this region may also be useful for definitively establishing linkage with one form of dyslexia. DNA probes in this chromosomal region should facilitate molecular structural analysis for elucidation of the nature of instability in this region, which is frequently associated with chromosomal aberrations.     

Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study

In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S_all statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.     

The keeshond defect in cardiac conotruncal development is oligogenic1

Earlier studies in the keeshond breed of dogs established that isolated conotruncal defects (CTDs) are a group of genetically and embryologically related cardiac malformations, including sub-clinical defects of the conal septum, conal ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus. The same spectrum occurs in some human families. In both species, inheritance of non-syndromic CTDs is usually complex and multifactorial inheritance has been assumed. Previous studies in the keeshond suggested that susceptibility to CTD is an autosomal recessive trait, with alleles at modifying loci affecting severity. Here we report results of a genome-wide scan for CTD linked loci in a keeshond × beagle F1 backcross pedigree in which 46 of 101 offspring had CTDs. Two-point linkage analysis identified regions of suggestive linkage on each of three chromosomes CFA2, CFA9, and CFA15. No single locus accounted for segregation of CTDs in the pedigree, ruling out a single autosomal susceptibility locus. Multipoint analysis with Genehunter resulted in a corrected LOD score of 3.7 at the locus on CFA9 and supported linkage to the loci on CFA2 and CFA15 (LOD scores of 2.71 and 3.03). Genehunter Twolocus analysis suggested that CTD-predisposing alleles of these three loci are necessary, at least in pairs, to produce CTD. The canine CTD-linked chromosome regions are orthologous to human regions HSA5q11-13, HSA5q31, HSA17q11-24, and HSA4q31. We excluded from the linked regions in the dog, a number of genes known to have a role in the etiology of CTDs and predict that continuing studies will identify CTD-predisposing genes not previously recognized.Electronic Supplementary Material Supplementary material is available for this article at ¹ Nucleotide sequence data reported here are available at GenBank under accession numbers: AY438631, AY438632, AY438633, AY438634, AY438635, AY438636, AY438630     

Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q.

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders characterized by insidiously progressive spastic weakness in the legs. Genetic loci for autosomal dominant HSP exist on chromosomes 2p, 14q, and 15q. These loci are excluded in 45% of autosomal dominant HSP kindreds, indicating the presence of additional loci for autosomal dominant HSP. We analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage between the disorder and microsatellite markers on chromosome 8q (maximum two-point LOD score 5.51 at recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant HSP on chromosome 8q23-24. Currently this locus spans 6.2 cM between D8S1804 and D8S1774 and includes several potential candidate genes. Identifying this novel HSP locus on chromosome 8q23-24 will facilitate discovery of this HSP gene, improve genetic counseling for families with linkage to this locus, and extend our ability to correlate clinical features with different HSP loci.