Dataset Information

Runs of homozygosity identify a recessive locus 12q21.31 for human adult height.

ABSTRACT:

Background

Runs of homozygosity (ROHs) have recently been proposed to have potential recessive significance for complex traits. Human adult height is a classic complex trait with heritability estimated up to 90%, and recessive loci that contribute to adult height variation have been identified.

Methods

Using the Affymetrix 500K array set, we performed a genome-wide ROHs analysis to identify genetic loci for adult height in a discovery sample including 998 unrelated Caucasian subjects from the midwest United States. For the significant ROHs identified, we replicated these findings in a family-based sample of 8385 Caucasian subjects from the Framingham Heart Study (FHS).

Results

Our results revealed one ROH, located in 12q21.31, that had a strong association with adult height variation both in the discovery (P=6.69x10(-6)) and replication samples (P=5.40x10(-5)). We further validated the presence of this ROH using the HapMap sample.

Conclusion

Our findings open a new avenue for identifying loci with recessive contributions to adult height variation. Further molecular and functional studies are needed to explore and clarify the potential mechanism.

SUBMITTER: Yang TL

PROVIDER: S-EPMC2913044 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Publications

Runs of homozygosity identify a recessive locus 12q21.31 for human adult height.

Yang Tie-Lin TL Guo Yan Y Zhang Li-Shu LS Tian Qing Q Yan Han H Papasian Christopher J CJ Recker Robert R RR Deng Hong-Wen HW

The Journal of clinical endocrinology and metabolism 20100513 8

<h4>Background</h4>Runs of homozygosity (ROHs) have recently been proposed to have potential recessive significance for complex traits. Human adult height is a classic complex trait with heritability estimated up to 90%, and recessive loci that contribute to adult height variation have been identified.<h4>Methods</h4>Using the Affymetrix 500K array set, we performed a genome-wide ROHs analysis to identify genetic loci for adult height in a discovery sample including 998 unrelated Caucasian subje ...[more]

PMID: 20466785

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Project description:IMPORTANCE The search for novel Alzheimer disease (AD) genes or pathologic mutations within known AD loci is ongoing. The development of array technologies has helped to identify rare recessive mutations among long runs of homozygosity (ROHs), in which both parental alleles are identical. Caribbean Hispanics are known to have an elevated risk for AD and tend to have large families with evidence of inbreeding. OBJECTIVE To test the hypothesis that the late-onset AD in a Caribbean Hispanic population might be explained in part by the homozygosity of unknown loci that could harbor recessive AD risk haplotypes or pathologic mutations. DESIGN We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses. SETTING A whole-genome case-control ROH study. PARTICIPANTS A Caribbean Hispanic data set of 547 unrelated cases (48.8% with familial AD) and 542 controls collected from a population known to have a 3-fold higher risk of AD vs non-Hispanics in the same community. Based on a Structure program analysis, our data set consisted of African Hispanic (207 cases and 192 controls) and European Hispanic (329 cases and 326 controls) participants. EXPOSURE Alzheimer disease risk genes. MAIN OUTCOMES AND MEASURES We calculated the total and mean lengths of the ROHs per sample. Global burden measurements among autosomal chromosomes were investigated in cases vs controls. Pools of overlapping ROH segments (consensus regions) were identified, and the case to control ratio was calculated for each consensus region. We formulated the tested hypothesis before data collection. RESULTS In total, we identified 17 137 autosomal regions with ROHs. The mean length of the ROH per person was significantly greater in cases vs controls (P?=?.0039), and this association was stronger with familial AD (P?=?.0005). Among the European Hispanics, a consensus region at the EXOC4 locus was significantly associated with AD even after correction for multiple testing (empirical P value 1 [EMP1], .0001; EMP2, .002; 21 AD cases vs 2 controls). Among the African Hispanic subset, the most significant but nominal association was observed for CTNNA3, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls). CONCLUSIONS AND RELEVANCE Our results show that ROHs could significantly contribute to the etiology of AD. Future studies would require the analysis of larger, relatively inbred data sets that might reveal novel recessive AD genes. The next step is to conduct sequencing of top significant loci in a subset of samples with overlapping ROHs.

Project description:Pedigree information was traditionally used to assess inbreeding. The availability of high-density marker panels provides an alternative to assess inbreeding, particularly in the presence of incomplete and error-prone pedigrees. Assessment of autozygosity across chromosomal segments using runs of homozygosity (ROH) has emerged as a valuable tool to estimate inbreeding due to its general flexibility and ability to quantify the chromosomal contribution to genome-wide inbreeding. Unfortunately, the identification of ROH segments is sensitive to the parameters used during the search process. These parameters are heuristically set, leading to significant variation in the results. The minimum length required to identify an ROH segment has major effects on the estimation of inbreeding and inbreeding depression, yet it is arbitrarily set. To overcome this limitation, a search algorithm to approximate mutation enrichment was developed to determine the minimum length of ROH segments. It consists of finding genome segments with significant effect differences in trait means between animals with high and low burdens of autozygous intervals with a specific length. The minimum length could be determined heuristically as the smallest interval at which a significant signal is detected. The proposed method was tested in an inbred Hereford cattle population genotyped for 30,220 SNPs. Phenotypes recorded for six traits were used for the approximation of mutation loads. The estimated minimum length was around 1 Mb for yearling weight (YW) and average daily gain (ADG) and 4 Mb for birth weight and weaning weight. These trait-specific thresholds estimated using the proposed method could be attributed to a trait-dependent effect of homozygosity. The detection of significant inbreeding effects was well aligned with the estimated thresholds, especially for YW and ADG. Although highly deleterious alleles are expected to be more frequent in recent inbreeding (long ROH), short ROH segments (<5 Mb) could contain a large number of less deleterious mutations with substantial joint effects on some traits (YW and ADG). Our results highlight the importance of accurate estimation of the ROH-based inbreeding and the necessity to consider a trait-specific minimum length threshold for the identification of ROH segments in inbreeding depression analyses. These thresholds could be determined using the proposed method provided the availability of phenotypic information.

Dataset Information

Runs of homozygosity identify a recessive locus 12q21.31 for human adult height.

Background

Methods

Results

Conclusion

Publications

Runs of homozygosity identify a recessive locus 12q21.31 for human adult height.

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