Identifying influential individuals in linkage analysis: Application to a quantitative trait locus detected in the COGA data

Once linkage is detected to a quantitative trait locus (QTL), the next step towards localizing the gene involved may be to identify those families, or individuals, in whom the putative mutations are segregating. In this paper, we describe a jackknife procedure for identifying individuals (and families) who contribute disproportionately to the linkage. Following initial detection of linkage to a QTL, the strategy involves sequentially removing each individual (or each family) from the analysis and recomputing the lod score associated with the linked region using data from all remaining subjects (or families). This procedure can be used to determine if particular observations have substantial impact on evidence for linkage. Identification of such observations may provide insights for further efforts to localize the QTL.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101831/1/1370170744_ftp.pd

Neural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene–Gene and Gene–Environment Interactions

BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results. OBJECTIVES: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation. METHODS: In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase. RESULTS: Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission. CONCLUSIONS: BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene–gene interactions in large data sets

Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants

BACKGROUND: Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. METHODS: We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive annotation to identify single variants which could confer ASD risk and also gene-based association analysis to identify sets of rare variants associated with ASD. RESULTS: We identified a significant over-representation of rare loss-of-function variants in genes previously associated with ASD, including a de novo premature stop variant in the well-established ASD candidate gene RBFOX1. Furthermore, ASD cases were more likely to have two damaging missense variants in candidate genes than controls. Finally, gene-based rare variant association implicates genes functioning in excitatory neurotransmission and neurite outgrowth and guidance pathways including CACNAD2, KCNH7, and NRXN1. CONCLUSIONS: We find suggestive evidence that rare variants in synaptic genes are associated with ASD and that loss-of-function mutations in ASD candidate genes are a major risk factor, and we implicate damaging mutations in glutamate signaling receptors and neuronal adhesion and guidance molecules. Furthermore, the role of de novo mutations in ASD remains to be fully investigated as we identified the first reported protein-truncating variant in RBFOX1 in ASD. Overall, this work, combined with others in the field, suggests a convergence of genes and molecular pathways underlying ASD etiology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13229-015-0034-z) contains supplementary material, which is available to authorized users

Novel quantitative trait locus is mapped to chromosome 12p11 for left ventricular mass in Dominican families: the Family Study of Stroke Risk and Carotid Atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Left ventricular mass (LVM) is an important risk factor for stroke and vascular disease. The genetic basis of LVM is unclear although a high heritability has been suggested. We sought to map quantitative trait loci (QTL) for LVM using large Dominican families.</p> <p>Methods</p> <p>Probands were selected from Dominican subjects of the population-based Northern Manhattan Study (NOMAS). LVM was measured by transthoracic echocardiography. A set of 405 microsatellite markers was used to screen the whole genome among 1360 subjects from 100 Dominican families who had complete phenotype data and DNA available. A polygenic covariate screening was run to identify the significant covariates. Variance components analysis was used to estimate heritability and to detect evidence for linkage, after adjusting for significant risk factors. Ordered-subset Analysis (OSA) was conducted to identify a more homogeneous subset for stratification analysis.</p> <p>Results</p> <p>LVM had a heritability of 0.58 in the studied population (p < 0.0001). The most significant evidence for linkage was found at chromosome 12p11 (MLOD = 3.11, empirical p = 0.0003) with peak marker at D12S1042. This linkage was significantly increased in a subset of families with the high average waist circumference (MLOD = 4.45, p = 0.0045 for increase in evidence for linkage).</p> <p>Conclusion</p> <p>We mapped a novel QTL near D12S1042 for LVM in Dominicans. Enhanced linkage evidence in families with larger waist circumference suggests that gene(s) residing within the QTL interact(s) with abdominal obesity to contribute to phenotypic variation of LVM. Suggestive evidence for linkage (LOD = 1.99) has been reported at the same peak marker for left ventricular geometry in a White population from the HyperGEN study, underscoring the importance of this QTL for left ventricular phenotype. Further fine mapping and validation studies are warranted to identify the underpinning genes.</p

A follow-up study for left ventricular mass on chromosome 12p11 identifies potential candidate genes

<p>Abstract</p> <p>Background</p> <p>Left ventricular mass (LVM) is an important risk factor for cardiovascular disease. Previously we found evidence for linkage to chromosome 12p11 in Dominican families, with a significant increase in a subset of families with high average waist circumference (WC). In the present study, we use association analysis to further study the genetic effect on LVM.</p> <p>Methods</p> <p>Association analysis with LVM was done in the one LOD critical region of the linkage peak in an independent sample of 897 Caribbean Hispanics. Genotype data were available on 7085 SNPs from 23 to 53 MB on chromosome 12p11. Adjustment was made for vascular risk factors and population substructure using an additive genetic model. Subset analysis by WC was performed to test for a difference in genetic effects between the high and low WC subsets.</p> <p>Results</p> <p>In the overall analysis, the most significant association was found to rs10743465, downstream of the <it>SOX5 </it>gene (p = 1.27E-05). Also, 19 additional SNPs had nominal p < 0.001. In the subset analysis, the most significant difference in genetic effect between those with high and low WC occurred with rs1157480 (p = 1.37E-04 for the difference in β coefficients), located upstream of <it>TMTC1</it>. Twelve additional SNPs in or near 6 genes had p < 0.001.</p> <p>Conclusions</p> <p>The current study supports previously identified evidence by linkage for a genetic effect on LVM on chromosome 12p11 using association analysis in population-based Caribbean Hispanic cohort. <it>SOX5 </it>may play an important role in the regulation of LVM. An interaction of <it>TMTC1 </it>with abdominal obesity may contribute to phenotypic variation of LVM.</p

High Density SNP Screen in A Large Multiplex Neural Tube Defect Family Refines Linkage to Loci at 7p21-Pter And 2q33.1-35

Neural tube defects (NTDs) are considered complex with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs (Rampersaud et al. 2005) demonstrated evidence of linkage to chromosomes 7 and 10. This screen included forty-four multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Candidate gene study revealed sex specific association between the OLR1 gene and carotid plaque

BACKGROUND AND PURPOSE: Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke. METHODS: For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study (NOMAS) were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in eleven lipid-related genes were genotyped. Plaque presence and plaque sub-phenotypes, including multiple, thick, irregular and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (p<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes. RESULTS: The most compelling finding is with the missense SNP rs11053646 (K167N) in the OLR1 gene, which encodes lectin-like oxidized LDL receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR=2.44~5.86, p=0.0003~0.0081) but not in men (OR=0.85~1.22 p=0.77~0.92). CONCLUSIONS: Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk

Genome-wide linkage and peak-wide association study of obesity-related quantitative traits in Caribbean Hispanics

Although obesity is more prevalent in Hispanics than non-Hispanic whites in the United States, little is known about the genetic etiology of the related traits in this population. To identify genetic loci influencing obesity in non-Mexican Hispanics, we performed a genome-wide linkage scan in 1,390 subjects from 100 Caribbean Hispanic families on six obesity-related quantitative traits: body mass index (BMI), body weight, waist circumference, waist-to-hip ratio, abdominal and average triceps skinfold thickness after adjusting for significant demographic and lifestyle factors. We then carried out an association analysis of the linkage peaks and the FTO gene in an independent community-based Hispanic subcohort ( N = 652, 64% Caribbean Hispanics) from the Northern Manhattan Study. Evidence of linkage was strongest on 1q43 with multipoint LOD score of 2.45 ( p = 0.0004) for body weight. Suggestive linkage evidence of LOD > 2.0 was also identified on 1q43 for BMI (LOD = 2.03), 14q32 for abdominal skinfold thickness (LOD = 2.17), 16p12 for BMI (LOD = 2.27) and weight (LOD = 2.26), and 16q23–24 for average triceps skinfold thickness (LOD = 2.32). In the association analysis of 6,440 single nucleotide polymorphisms (SNPs) under 1-LOD unit down regions of our linkage peaks on chromosome 1q43 and 16p12 as well as in the FTO gene, we found that two SNPs (rs6665519 and rs669231) on 1q43 and one FTO SNP (rs12447427) were significantly associated with BMI or body weight after adjustment for multiple testing. Our results suggest that in addition to FTO , multiple genetic loci, particularly those on 1q43 region, may contribute to the variations in obesity-related quantitative traits in Caribbean Hispanics

Genomewide Linkage and Peakwide Association Analyses of Carotid Plaque in Caribbean Hispanics

BACKGROUND AND PURPOSE: Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples. METHODS: B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18 904 single nucleotide polymorphisms under the 1-logarithm of odds unit down regions of linkage peaks in an independent community-based data set (N=941, 41% Dominicans) from the Northern Manhattan Study. RESULTS: After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h2=0.50±0.14, P<0.0001) and plaque area (h2=0.17±0.04, P<0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores ≥2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near SOX6, FSD2, AP3S2, EFTUD1, and MYOD1 were associated with carotid plaque traits with a nominal P≤0.0005 in the Northern Manhattan Study data set and with a P≤0.01 in Northern Manhattan Study Dominican subset. CONCLUSIONS: Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The SOX6 gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings