A Genome-Wide Linkage Scan for Age at Menarche in Three Populations of European Descent

Context: Age at menarche (AAM) is an important trait both biologically and socially, a clearly defined event in female pubertal development, and has been associated with many clinically significant phenotypes. Objective: The objective of the study was to identify genetic loci influencing variation in AAM in large population-based samples from three countries. Design/Participants: Recalled AAM data were collected from 13,697 individuals and 4,899 pseudoindependent sister-pairs from three different populations (Australia, The Netherlands, and the United Kingdom) by mailed questionnaire or interview. Genome-wide variance components linkage analysis was implemented on each sample individually and in combination. Results: The mean, sd, and heritability of AAM across the three samples was 13.1 yr, 1.5 yr, and 0.69, respectively. No loci were detected that reached genome-wide significance in the combined analysis, but a suggestive locus was detected on chromosome 12 (logarithm of the odds = 2.0). Three loci of suggestive significance were seen in the U.K. sample on chromosomes 1, 4, and 18 (logarithm of the odds = 2.4, 2.2 and 3.2, respectively). Conclusions: There was no evidence for common highly penetrant variants influencing AAM. Linkage and association suggest that one trait locus for AAM is located on chromosome 12, but further studies are required to replicate these results.

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The molecular genetics of hand preference revisited

10.1101/447177 ◽

2018 ◽

Cited By ~ 1

Author(s):

Carolien G.F. de Kovel ◽

Clyde Francks

Keyword(s):

Complex Traits ◽

Large Population ◽

Enrichment Analysis ◽

Hand Preference ◽

Population Based ◽

Gene Set Enrichment Analysis ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractHand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the gene MAP2 in handedness.

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Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity

Nutrients ◽

10.3390/nu13061984 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1984

Author(s):

Majid Nikpay ◽

Sepehr Ravati ◽

Robert Dent ◽

Ruth McPherson

Keyword(s):

Quantitative Trait Locus ◽

Quantitative Trait ◽

Rare Variants ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search ◽

Risk Snps ◽

Trait Locus ◽

Genomic Regions ◽

Eqtl Data

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

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Genomic Variations in Susceptibility to Intracranial Aneurysm in the Korean Population

Journal of Clinical Medicine ◽

10.3390/jcm8020275 ◽

2019 ◽

Vol 8 (2) ◽

pp. 275 ◽

Cited By ~ 8

Author(s):

Eun Hong ◽

Bong Kim ◽

Steve Cho ◽

Jin Yang ◽

Hyuk Choi ◽

...

Keyword(s):

Intracranial Aneurysm ◽

Association Studies ◽

Large Population ◽

Genome Wide Association ◽

Korean Population ◽

Genome Wide Association Studies ◽

Medicine Research ◽

Genome Wide ◽

A Genome ◽

Significant Difference

Genome-wide association studies found genetic variations with modulatory effects for intracranial aneurysm (IA) formations in European and Japanese populations. We aimed to identify the susceptibility of single nucleotide polymorphisms (SNPs) to IA in a Korean population consisting of 250 patients, and 294 controls using the Asian-specific Axiom Precision Medicine Research Array. Twenty-nine SNPs reached a genome-wide significance threshold (5 × 10−8). The rs371331393 SNP, with a stop-gain function of ARHGAP32 (11q24.3), showed the most significant association with the risk of IA (OR = 43.57, 95% CI: 21.84–86.95; p = 9.3 × 10−27). Eight out of 29 SNPs—GBA (rs75822236), TCF24 (rs112859779), OLFML2A (rs79134766), ARHGAP32 (rs371331393), CD163L1 (rs138525217), CUL4A (rs74115822), LOC102724084 (rs75861150), and LRRC3 (rs116969723)—demonstrated sufficient statistical power greater than or equal to 0.8. Two previously reported SNPs, rs700651 (BOLL, 2q33.1) and rs6841581 (EDNRA, 4q31.22), were validated in our GWAS (Genome-wide association study). In a subsequent analysis, three SNPs showed a significant difference in expressions: the rs6741819 (RNF144A, 2p25.1) was down-regulated in the adrenal gland tissue (p = 1.5 × 10−6), the rs1052270 (TMOD1. 9q22.33) was up-regulated in the testis tissue (p = 8.6 × 10−10), and rs6841581 (EDNRA, 4q31.22) was up-regulated in both the esophagus (p = 5.2 × 10−12) and skin tissues (1.2 × 10−6). Our GWAS showed novel candidate genes with Korean-specific variations in IA formations. Large population based studies are thus warranted.

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Complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl rat chromosome 17

Physiological Genomics ◽

10.1152/physiolgenomics.00275.2004 ◽

2005 ◽

Vol 21 (1) ◽

pp. 112-116 ◽

Cited By ~ 19

Author(s):

Myrian Grondin ◽

Vasiliki Eliopoulos ◽

Raphaelle Lambert ◽

Yishu Deng ◽

Anita Ariyarajah ◽

...

Keyword(s):

Blood Pressure ◽

Quantitative Trait Locus ◽

Quantitative Trait ◽

Congenic Strain ◽

Chromosome 17 ◽

Congenic Strains ◽

Genome Wide ◽

A Genome ◽

Trait Locus ◽

Negative Controls

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the ±2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower ( P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different ( P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of ∼15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of “negative” controls in physically mapping a QTL by congenic strains.

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A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Journal of the American Academy of Child & Adolescent Psychiatry ◽

10.1016/j.jaac.2016.05.025 ◽

2016 ◽

Vol 55 (10) ◽

pp. 896-905.e6 ◽

Cited By ~ 68

Author(s):

Christel M. Middeldorp ◽

Anke R. Hammerschlag ◽

Klaasjan G. Ouwens ◽

Maria M. Groen-Blokhuis ◽

Beate St. Pourcain ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Meta Analysis ◽

Population Based ◽

Genome Wide Association ◽

Hyperactivity Disorder ◽

Genome Wide ◽

A Genome

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A quantitative trait locus influencing estrogen levels maps to a region homologous to human chromosome 20

Physiological Genomics ◽

10.1152/physiolgenomics.2001.5.2.75 ◽

2001 ◽

Vol 5 (2) ◽

pp. 75-80 ◽

Cited By ~ 11

Author(s):

LISA J. MARTIN ◽

JOHN BLANGERO ◽

JEFFREY ROGERS ◽

MICHAEL C. MAHANEY ◽

JAMES E. HIXSON ◽

...

Keyword(s):

Quantitative Trait Locus ◽

Human Chromosome ◽

Quantitative Trait ◽

Potential Candidate ◽

General Pedigree ◽

Genome Wide ◽

A Genome ◽

Component Approach ◽

Trait Locus ◽

Variance Component Approach

Estrogen, a steroid hormone, regulates reproduction and has been implicated in several diseases. We performed a genome-wide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in estrogen levels in baboons. A microsatellite polymorphism, D20S171, located on human chromosome 20q13.11, showed strong evidence of linkage with a LOD score of 3.06 ( P = 0.00009). This region contains several potential candidate genes including melanocortin 3 receptor ( MC3R), cytochrome P-450 subfamily XXIV ( CYP24), and breast carcinoma amplified sequence ( BCAS1). This is the first evidence of a quantitative trait locus with a significant effect on estrogen.

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A Genome Segment on Mouse Chromosome 12 Determines Maxillary Growth

Journal of Dental Research ◽

10.1177/154405910708601212 ◽

2007 ◽

Vol 86 (12) ◽

pp. 1203-1206 ◽

Cited By ~ 6

Author(s):

J. Oh ◽

C.J. Wang ◽

M. Poole ◽

E. Kim ◽

R.C. Davis ◽

...

Keyword(s):

Mouse Chromosome ◽

Chromosome 12 ◽

Mouse Strains ◽

Snout Length ◽

Face Width ◽

Maxillofacial Development ◽

A Genome ◽

Imaging Results ◽

Trait Locus ◽

Anterior Posterior

The primary and modifier genes that regulate normal maxillofacial development are unknown. Previous quantitative trait locus (QTL) analyses using the F2 progeny of 2 mouse strains, DBA/2J (short snout/wide face) and C57BL/6J (long snout/narrow face), revealed a significant logarithm-of-odds (LOD) score for snout length on mouse chromosome 12 at 44 centimorgan (cM). We further sought to validate this locus contributing to anterior-posterior dimensions of the upper mid-face at the D12Mit7 marker in a 44-centimorgan portion of chromosome 12. Congenic mice carrying introgressed DNA from DBA/2J on a C57BL/6J background were selected for submental vertex cephalometric imaging. Results confirmed QTLs, determining that short snout length (P < 0.05) and face width relative to snout length (P < 0.01) were present in the 44-cM region of chromosome 12. We conclude that one or more genes contributing to the shape of the maxillary complex are located near 44 cM of mouse chromosome 12.

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Association of CNVs with methylation variation

npj Genomic Medicine ◽

10.1038/s41525-020-00145-w ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Xinghua Shi ◽

Saranya Radhakrishnan ◽

Jia Wen ◽

Jin Yun Chen ◽

Junjie Chen ◽

...

Keyword(s):

Association Studies ◽

Copy Number Variants ◽

Cpg Methylation ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Cellular Phenotype ◽

Genome Wide ◽

A Genome ◽

Physical Interactions ◽

Trait Locus

Abstract Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long-range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype.

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Association mapping and genetic dissection of drought-induced canopy temperature differences in rice

Journal of Experimental Botany ◽

10.1093/jxb/erz527 ◽

2019 ◽

Vol 71 (4) ◽

pp. 1614-1627 ◽

Cited By ~ 2

Author(s):

Giovanni Melandri ◽

Ankush Prashar ◽

Susan R McCouch ◽

Gerard van der Linden ◽

Hamlyn G Jones ◽

...

Keyword(s):

Genetic Variation ◽

Grain Yield ◽

Canopy Temperature ◽

Leaf Temperature ◽

Genetic Dissection ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome ◽

Snp Map ◽

Trait Locus

Abstract Drought-stressed plants display reduced stomatal conductance, which results in increased leaf temperature by limiting transpiration. In this study, thermal imaging was used to quantify the differences in canopy temperature under drought in a rice diversity panel consisting of 293 indica accessions. The population was grown under paddy field conditions and drought stress was imposed for 2 weeks at flowering. The canopy temperature of the accessions during stress negatively correlated with grain yield (r= –0.48) and positively with plant height (r=0.56). Temperature values were used to perform a genome-wide association (GWA) analysis using a 45K single nucleotide polynmorphism (SNP) map. A quantitative trait locus (QTL) for canopy temperature under drought was detected on chromosome 3 and fine-mapped using a high-density imputed SNP map. The candidate genes underlying the QTL point towards differences in the regulation of guard cell solute intake for stomatal opening as the possible source of temperature variation. Genetic variation for the significant markers of the QTL was present only within the tall, low-yielding landraces adapted to drought-prone environments. The absence of variation in the shorter genotypes, which showed lower leaf temperature and higher grain yield, suggests that breeding for high grain yield in rice under paddy conditions has reduced genetic variation for stomatal response under drought.

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