QTLs for height: results of a full genome scan in Dutch sibling pairs

Willemsen, Gonneke; Boomsma, Dorret I.; Beem, A. Leo; Vink, Jacqueline M.; Slagboom, P. Eline; Posthuma, Daniëlle

doi:10.1038/sj.ejhg.5201229

Cited by 29 publications

(31 citation statements)

References 33 publications

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“…This is consistent with the findings of this as well as other linkage studies on height (e.g., Hirschhorn et al 2001;Xu et al 2002;Wiltshire et al 2002). Typically as shown in all of the genome-wide linkage scans for height so far, among all the regions reported, only very few reached the significance threshold for linkage (LOD>3.0) (for review see Willemsen et al 2004), implicating the difficulty to detect height genes of ''major effects''. Although our study had achieved the largest sample size and most (Sammalisto et al 2005) likely, the highest statistical power in all the genomewide linkage scans for height, we only detected three regions, 9q22, Xq24, and Xp22, of statistically significant linkage to height.…”

Section: Xp22 Xq24supporting

confidence: 90%

Genetic linkage of human height is confirmed to 9q22 and Xq24

et al. 2006

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Human height is an important and heritable trait. Our previous two genome-wide linkage studies using 630 (WG1 study) and an extended sample of 1,816 Caucasians (WG2 study) identified 9q22 [maximum LOD score (MLS)=2.74 in the WG2 study] and preliminarily confirmed Xq24 (two-point LOD score=1.91 in the WG1 study, 2.64 in the WG2 study) linked to height. Here, with a much further extended large sample containing 3,726 Caucasians, we performed a new genome-wide linkage scan and confirmed, in high significance, the two regions' linkage to height. An MLS of 4.34 was detected on 9q22 and a two-point LOD score of 5.63 was attained for Xq24. In an independent sub-sample (i.e., the subjects not involved in the WG1 and WG2 studies), the two regions also achieved significant empirical P values (0.002 and 0.004, respectively) for "region-wise" linkage confirmation. Importantly, the two regions were replicated on a genotyping platform different from the WG1 and WG2 studies (i.e., a different set of markers and different genotyping instruments). Interestingly, 9q22 harbors the ROR2 gene, which is required for growth plate development, and Xq24 was linked to short stature. With the largest sample from a single population of the same ethnicity in the field of linkage studies for complex traits, our current study, together with two previous ones, provided overwhelming evidence substantiating 9q22 and Xq24 for height variation. In particular, our three consecutive whole genome studies are uniquely valuable as they represent the first practical (rather than simulated) example of how significant increase in sample size may improve linkage detection for human complex traits.

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Section: Xp22 Xq24supporting

confidence: 90%

Genetic linkage of human height is confirmed to 9q22 and Xq24

et al. 2006

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“…Human adult height has been suggested to be highly heritable, with heritability estimates (h 2 ) ranging from 0.5 to 0.9 (Mukhopadhyay and Weeks 2003;Willemsen et al 2004) in various populations and with an h 2 of 0.7 in the Samoan islands (unpublished data). Our simulation study shows that, if the heritability that is explained by a single trait locus ranges from 0.7 to 0.175, the power to detect a linkage signal (genome-wide α = 0.05) to adult height in the current study sample ranges from 31% to 14%.…”

Section: Susceptibility Loci For Adult Heightmentioning

confidence: 99%

“…These fairly low power estimates suggest that additional chromosome regions not detected in the current study might be of great importance for variation in adult height in the studied population. Since the first genome-wide linkage scans for height were performed in 2001 (Hirschhorn et al 2001;Perola et al 2001), several susceptibility loci for height have been reported [for a recent overview see Perola et al (2007)], but, as for most complex phenotypes, only some have been successfully replicated by further studies (Liu et al 2004(Liu et al , 2006Willemsen et al 2004;Sale et al 2005;Shmulewitz et al 2006). The most promising susceptibility loci for height (Score.Max p = 0.005) detected in our current study of sib-pairs from American Samoa was located on chromosome 9q31 at marker D9S1690.…”

Section: Susceptibility Loci For Adult Heightmentioning

confidence: 99%

Applying Novel Genome-Wide Linkage Strategies to Search for Loci Influencing Type 2 Diabetes and Adult Height in American Samoa

Åberg¹,

Sun²,

Smelser³

et al. 2008

Human Biology

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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 S all implemented in Allegro and a novel twodimensional 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. NIH Public Access Author ManuscriptHum Biol. Author manuscript; available in PMC 2013 July 04. DIABETES; STATURE; LINKAGE ANALYSIS; TWO-DIMENSIONAL LINKAGE; QUANTITATIVE TRAIT LOCUS; QTL-ALL SOFTWAREType 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance and dysfunction of the pancreatic beta cells. The disease results from a complex interaction of genetic and environmental factors and is strongly associated with obesity and modernized lifestyle. The disease has emerged to become a major public health problem. In 2000 T2DM affected 151 million people globally. This number is predicted to increase to 221 million in 2010, and the greatest proportional increase is expected to occur in regions adopting a modernized lifestyle, such as Africa and Asia with a 50% and 57% increase, respectively (Zimmet et al. 2001).A genetic contribution to the development of T2DM is supported by family aggregation with increased risk of developing the disease for first-degree relatives of probands and a greater concordance between affected monozygotic twins compared to dizygotic twins (Barroso 2005). In addition, disease prevalence varies substantially between ethnic groups living in the same environment, suggesting racial disparity for T2DM (Carulli et al. 2005).In this study we search for linkage to T2DM i...

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“…However, the list of genes and allelic variants involved in the determination of BS and BG variation is far from being complete. Several genome-wide scans have been conducted to identify susceptibility loci for bone size (e.g., Koller et al 2001;Deng et al 2003b) and adult height variation (e.g., Mukhopadhyay et al 2003;Willemsen et al 2004). With a few exceptions the results of the linkage analyses are so far largely inconsistent.…”

Section: Introductionmentioning

confidence: 99%

Strong association between polymorphisms in ANKH locus and skeletal size traits

et al. 2006

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Loss of bone strength is the main determinant of bone fragility. Bone strength is directly dependent on bone size (BS). A substantial portion of BS variation is attributable to genetic effects. However, the list of genes and allelic variants involved in the determination of BS variation is far from being complete. Polymorphisms in the ANKH gene have been shown to be associated with radiographic hand BS-related phenotypes. The present study examined the possible association of the ANKH gene with skeletal size and shape in order to test the universality of the ANKH effect on BS traits. Our sample consisted of a total of 212 ethnically homogeneous nuclear families (743 individuals) of European origin. Each individual was measured for body height, weight, and several other anthropometrical measurements, and genotyped for nine polymorphic markers (the average heterozygosity level was 0.4). We observed significant associations with practically all the anthropometrical phenotypes studied. More specifically, we found associations with body weight and height, limb length (P

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QTLs for height: results of a full genome scan in Dutch sibling pairs

Cited by 29 publications

References 33 publications

Genetic linkage of human height is confirmed to 9q22 and Xq24

Genetic linkage of human height is confirmed to 9q22 and Xq24

Applying Novel Genome-Wide Linkage Strategies to Search for Loci Influencing Type 2 Diabetes and Adult Height in American Samoa

Strong association between polymorphisms in ANKH locus and skeletal size traits

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