Publications by authors named "Paul J Gallins"

20 Publications

  • Page 1 of 1

A New Liver Expression Quantitative Trait Locus Map From 1,183 Individuals Provides Evidence for Novel Expression Quantitative Trait Loci of Drug Response, Metabolic, and Sex-Biased Phenotypes.

Clin Pharmacol Ther 2020 06 30;107(6):1383-1393. Epub 2020 Jan 30.

Eshelman School of Pharmacy and Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Expression quantitative trait locus (eQTL) studies in human liver are crucial for elucidating how genetic variation influences variability in disease risk and therapeutic outcomes and may help guide strategies to obtain maximal efficacy and safety of clinical interventions. Associations between expression microarray and genome-wide genotype data from four human liver eQTL studies (n = 1,183) were analyzed. More than 2.3 million cis-eQTLs for 15,668 genes were identified. When eQTLs were filtered against a list of 1,496 drug response genes, 187,829 cis-eQTLs for 1,191 genes were identified. Additionally, 1,683 sex-biased cis-eQTLs were identified, as well as 49 and 73 cis-eQTLs that colocalized with genome-wide association study signals for blood metabolite or lipid levels, respectively. Translational relevance of these results is evidenced by linking DPYD eQTLs to differences in safety of chemotherapy, linking the sex-biased regulation of PCSK9 expression to anti-lipid therapy, and identifying the G-protein coupled receptor GPR180 as a novel drug target for hypertriglyceridemia.
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http://dx.doi.org/10.1002/cpt.1751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816646PMC
June 2020

A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure.

Cell Rep 2018 Apr;23(2):327-336

Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.

Fibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed, but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21's mechanisms and therapeutic potential.
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http://dx.doi.org/10.1016/j.celrep.2018.03.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912948PMC
April 2018

Editor's Highlight: Comparative Dose-Response Analysis of Liver and Kidney Transcriptomic Effects of Trichloroethylene and Tetrachloroethylene in B6C3F1 Mouse.

Toxicol Sci 2017 Nov;160(1):95-110

Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas.

Trichloroethylene (TCE) and tetrachloroethylene (PCE) are ubiquitous environmental contaminants and occupational health hazards. Recent health assessments of these agents identified several critical data gaps, including lack of comparative analysis of their effects. This study examined liver and kidney effects of TCE and PCE in a dose-response study design. Equimolar doses of TCE (24, 80, 240, and 800 mg/kg) or PCE (30, 100, 300, and 1000 mg/kg) were administered by gavage in aqueous vehicle to male B6C3F1/J mice. Tissues were collected 24 h after exposure. Trichloroacetic acid (TCA), a major oxidative metabolite of both compounds, was measured and RNA sequencing was performed. PCE had a stronger effect on liver and kidney transcriptomes, as well as greater concentrations of TCA. Most dose-responsive pathways were common among chemicals/tissues, with the strongest effect on peroxisomal β-oxidation. Effects on liver and kidney mitochondria-related pathways were notably unique to PCE. We performed dose-response modeling of the transcriptomic data and compared the resulting points of departure (PODs) to those for apical endpoints derived from long-term studies with these chemicals in rats, mice, and humans, converting to human equivalent doses using tissue-specific dosimetry models. Tissue-specific acute transcriptional effects of TCE and PCE occurred at human equivalent doses comparable to those for apical effects. These data are relevant for human health assessments of TCE and PCE as they provide data for dose-response analysis of the toxicity mechanisms. Additionally, they provide further evidence that transcriptomic data can be useful surrogates for in vivo PODs, especially when toxicokinetic differences are taken into account.
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http://dx.doi.org/10.1093/toxsci/kfx165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837274PMC
November 2017

Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity.

Am J Respir Crit Care Med 2018 01;197(1):79-93

2 Cystic Fibrosis/Pulmonary Research and Treatment Center, Marsico Lung Institute, School of Medicine, and.

Rationale: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known.

Objectives: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing "in vivo" CF airway epithelial gene expression complemented with genome-wide association study (GWAS) data.

Methods: Nasal mucosal RNA from 134 patients with CF was used for RNA sequencing. We tested for associations of transcriptomic (gene expression) data with a quantitative phenotype of CF lung disease severity. Pathway analysis of CF GWAS data (n = 5,659 patients) was performed to identify novel pathways and assess the concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested.

Measurements And Main Results: Significant evidence of heritable gene expression was identified. Gene expression pathways relevant to airway mucosal host defense were significantly associated with CF lung disease severity, including viral infection, inflammation/inflammatory signaling, lipid metabolism, apoptosis, ion transport, Phe508del CFTR processing, and innate immune responses, including HLA (human leukocyte antigen) genes. Ion transport and CFTR processing pathways, as well as HLA genes, were identified across differential gene expression and GWAS signals.

Conclusions: Transcriptomic analyses of CF airway epithelia, coupled to genomic (GWAS) analyses, highlight the role of heritable host defense variation in determining the pathophysiology of CF lung disease. The identification of these pathways provides opportunities to pursue targeted interventions to improve CF lung health.
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http://dx.doi.org/10.1164/rccm.201701-0134OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765386PMC
January 2018

Genomic Characterization of Metformin Hepatic Response.

PLoS Genet 2016 Nov 30;12(11):e1006449. Epub 2016 Nov 30.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.

Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.
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http://dx.doi.org/10.1371/journal.pgen.1006449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130177PMC
November 2016

Novel variation at chr11p13 associated with cystic fibrosis lung disease severity.

Hum Genome Var 2016 7;3:16020. Epub 2016 Jul 7.

Marsico Lung Institute, CF/Pulmonary Research and Treatment Center, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA.

Published genome-wide association studies (GWASs) identified an intergenic region with regulatory features on chr11p13 associated with cystic fibrosis (CF) lung disease severity. Targeted resequencing in n=377, followed by imputation to n=6,365 CF subjects, was used to identify unrecognized genetic variants (including indels and microsatellite repeats) associated with phenotype. Highly significant associations were in strong linkage disequilibrium and were seen only in Phe508del homozygous CF subjects, indicating a CFTR genotype-specific mechanism.
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http://dx.doi.org/10.1038/hgv.2016.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935763PMC
July 2016

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

Nat Commun 2015 Sep 29;6:8382. Epub 2015 Sep 29.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.
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http://dx.doi.org/10.1038/ncomms9382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589222PMC
September 2015

Polymorphisms associated with expression of BPIFA1/BPIFB1 and lung disease severity in cystic fibrosis.

Am J Respir Cell Mol Biol 2015 Nov;53(5):607-14

1 Centre for Heart Lung Innovation, UBC and St. Paul's Hospital, Vancouver, British Columbia.

BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are putative innate immune molecules expressed in the upper airways. Because of their hypothesized roles in airway defense, these molecules may contribute to lung disease severity in cystic fibrosis (CF). We interrogated BPIFA1/BPIFB1 single-nucleotide polymorphisms in data from an association study of CF modifier genes and found an association of the G allele of rs1078761 with increased lung disease severity (P = 2.71 × 10(-4)). We hypothesized that the G allele of rs1078761 is associated with decreased expression of BPIFA1 and/or BPIFB1. Genome-wide lung gene expression and genotyping data from 1,111 individuals with lung disease, including 51 patients with CF, were tested for associations between genotype and BPIFA1 and BPIFB1 gene expression levels. Findings were validated by quantitative PCR in a subset of 77 individuals. Western blotting was used to measure BPIFA1 and BPIFB1 protein levels in 93 lung and 101 saliva samples. The G allele of rs1078761 was significantly associated with decreased mRNA levels of BPIFA1 (P = 4.08 × 10(-15)) and BPIFB1 (P = 0.0314). These findings were confirmed with quantitative PCR and Western blotting. We conclude that the G allele of rs1078761 may be detrimental to lung function in CF owing to decreased levels of BPIFA1 and BPIFB1.
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http://dx.doi.org/10.1165/rcmb.2014-0182OCDOI Listing
November 2015

Linkage and association of successful aging to the 6q25 region in large Amish kindreds.

Age (Dordr) 2013 Aug 7;35(4):1467-77. Epub 2012 Jul 7.

Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute of Human Genomics, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, Room 414, Miami, FL 33136, USA.

Successful aging (SA) is a multidimensional phenotype involving living to older age with high physical function, preserved cognition, and continued social engagement. Several domains underlying SA are heritable, and identifying health-promoting polymorphisms and their interactions with the environment could provide important information regarding the health of older adults. In the present study, we examined 263 cognitively intact Amish individuals age 80 and older (74 SA and 189 "normally aged") all of whom are part of a single 13-generation pedigree. A genome-wide association study of 630,309 autosomal single nucleotide polymorphisms (SNPs) was performed and analyzed for linkage using multipoint analyses and for association using the modified quasi-likelihood score test. There was evidence for linkage on 6q25-27 near the fragile site FRA6E region with a dominant model maximum multipoint heterogeneity LOD score = 3.2. The 1-LOD-down support interval for this linkage contained one SNP for which there was regionally significant evidence of association (rs205990, p = 2.36 × 10(-5)). This marker survived interval-wide Bonferroni correction for multiple testing and was located between the genes QKI and PDE10A. Other areas of chromosome 6q25-q27 (including the FRA6E region) contained several SNPs associated with SA (minimum p = 2.89 × 10(-6)). These findings suggest potentially novel genes in the 6q25-q27 region linked and associated with SA in the Amish; however, these findings should be verified in an independent replication cohort.
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http://dx.doi.org/10.1007/s11357-012-9447-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705095PMC
August 2013

Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

Neurology 2012 Jul 20;79(3):221-8. Epub 2012 Jun 20.

Department of Neuroscience, Biostatistics Unit, Mayo Clinic Florida, Jacksonville, FL, USA.

Objective: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.

Methods: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.

Results: CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).

Conclusions: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
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http://dx.doi.org/10.1212/WNL.0b013e3182605801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398432PMC
July 2012

The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.

Retina 2012 Sep;32(8):1486-91

Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.

Purpose: To identify genetic associations between specific risk genes and bilateral advanced age-related macular degeneration (AMD) in a retrospective, observational case series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830 patients with choroidal neovascularization in at least 1 eye.

Methods: Patients underwent clinical examination and fundus photography. The images were subsequently graded using a modified grading system adapted from the Age-Related Eye Disease Study. Genetic analysis was performed to identify genotypes at 4 AMD-associated variants (ARMS2 A69S, CFH Y402H, C3 R102G, and CFB R32Q) in these patients.

Results: There were no statistically significant relationships between clinical findings and genotypes at CFH, C3, and CFB. The genotype at ARMS2 correlated with bilateral advanced AMD using a variety of comparisons: unilateral geographic atrophy versus bilateral geographic atrophy (P = 0.08), unilateral choroidal neovascularization versus bilateral choroidal neovascularization (P = 9.0 × 10(-8)), and unilateral late AMD versus bilateral late AMD (P = 5.9 × 10(-8)).

Conclusion: In this series, in patients with geographic atrophy or choroidal neovascularization in at least 1 eye, the ARMS2 A69S substitution strongly associated with geographic atrophy or choroidal neovascularization in the fellow eye. The ARMS2 A69S substitution may serve as a marker for bilateral advanced AMD.
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http://dx.doi.org/10.1097/IAE.0b013e318240a540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269218PMC
September 2012

Vitamin D receptor and Alzheimer's disease: a genetic and functional study.

Neurobiol Aging 2012 Aug 4;33(8):1844.e1-9. Epub 2012 Feb 4.

Hussman Institute for Human Genomics, University of Miami Miller School of Medicine 1501 NW 10 Ave, Miami, Florida, USA.

Genetic studies on late-onset Alzheimer's disease (AD) have repeatedly mapped susceptibility loci onto chromosome 12q13, encompassing the vitamin D receptor (VDR) gene. Epidemiology studies have indicated vitamin D insufficiency as a risk factor for AD. Given that VDR is the major mediator for vitamin D's actions, we sought to clarify the role of VDR in late-onset AD. We conducted an association study in 492 late-onset AD cases and 496 controls with 80 tagging single nucleotide polymorphisms (SNPs). The strongest association was found at a promoter SNP rs11568820 (P = 9.1 × 10(-6), odds ratio (OR) = 1.69), which resides within the transcription factor Cdx-2 binding site and the SNP has been also known as CDX2. The risk-allele at rs11568820 is associated with lower VDR promoter activity (p < 10(-11)). The overexpression of VDR or vitamin D treatment suppressed amyloid precursor protein (APP) transcription in neuroblastoma cells (p < 0.001). We provide both statistical evidence and functional data suggesting VDR confers genetic risk for AD. Our findings are consistent with epidemiology studies suggesting that vitamin D insufficiency increases the risk of developing AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.12.038DOI Listing
August 2012

Mitochondrial haplogroup X is associated with successful aging in the Amish.

Hum Genet 2012 Feb 13;131(2):201-8. Epub 2011 Jul 13.

Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, FL 33136, USA.

Avoiding disease, maintaining physical and cognitive function, and continued social engagement in long-lived individuals describe successful aging (SA). Mitochondrial lineages described by patterns of common genetic variants ("haplogroups") have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on SA in an Amish community sample. Cognitively intact volunteers aged ≥80 years (n = 261) were enrolled in a door-to-door survey of Amish communities in Indiana and Ohio. Individuals scoring in the top third for lower extremity function, needing little assistance with self-care tasks, having no depression symptoms, and expressing high life satisfaction were considered SA (n = 74). The remainder (n = 187) were retained as controls. These individuals descend from 51 matrilines in a single 13-generation pedigree. Mitochondrial haplogroups were assigned using the ten mitochondrial single nucleotide polymorphisms (mtSNPs) defining the nine most common European haplogroups. An additional 17 mtSNPs from a genome-wide association panel were also investigated. Associations between haplogroups, mtSNPs, and SA were determined by logistic regression models accounting for sex, age, body mass index, and matriline via generalized estimating equations. SA cases were more likely to carry Haplogroup X (OR = 7.56, p = 0.0015), and less likely to carry Haplogroup J (OR = 0.40, p = 0.0003). Our results represent a novel association of Haplogroup X with SA and suggest that variants in the mitochondrial genome may promote maintenance of both physical and cognitive function in older adults.
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http://dx.doi.org/10.1007/s00439-011-1060-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834861PMC
February 2012

Successful aging shows linkage to chromosomes 6, 7, and 14 in the Amish.

Ann Hum Genet 2011 Jul;75(4):516-28

Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.

Successful aging (SA) is a multidimensional phenotype involving preservation of cognitive ability, physical function, and social engagement throughout life. Multiple components of SA are heritable, supporting a genetic component. The Amish are genetically and socially isolated with homogeneous lifestyles, making them a suitable population for studying the genetics of SA. DNA and measures of SA were collected on 214 cognitively intact Amish individuals over age 80. Individuals were grouped into a 13-generation pedigree using the Anabaptist Genealogy Database. A linkage screen of 5944 single nucleotide polymorphisms (SNPs) was performed using 12 informative subpedigrees with an affected-only 2-point and multipoint linkage analysis. Eleven SNPs produced 2-point LOD scores >2, suggestive of linkage. Multipoint linkage analyses, allowing for heterogeneity, detected significant LOD scores on chromosomes 6 (HLOD = 4.50), 7 (LOD*= 3.11), and 14 (HLOD = 4.17), suggesting multiple new loci underlying SA.
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http://dx.doi.org/10.1111/j.1469-1809.2011.00658.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756593PMC
July 2011

A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

Ann Hum Genet 2011 May;75(3):351-8

Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA.

Parkinson disease (PD) is a common complex neurodegenerative disorder with an underlying genetic etiology that has been difficult to dissect. Although some PD risk genes have been discovered, most of the underlying genetic etiology remains unknown. To further elucidate the genetic component, we have undertaken a genome-wide linkage screen in an isolated founder population of Amish living in the Midwestern United States. We performed tests for linkage and for association using a marker set of nearly 6000 single-nucleotide polymorphisms. Parametric multipoint linkage analysis generated a logarithm of the odds of linkage (LOD) score of 2.44 on chromosome 6 in the SYNE1 gene, approximately 8 Mbp from the PARK2 gene. In a different region on chromosome 6 (∼67 Mbp from PARK2) an association was found for rs4302647 (p < 4.0 × 10(-6) ), which is not within 300 kb of any gene. While the association exceeds Bonferroni correction, it may yet represent a false positive due to the small sample size and the low minor allele frequency. The minor allele frequency in affecteds is 0.07 compared to 0.01 in unaffecteds. Taken together, these results support involvement of loci on chromosome 6 in the genetic etiology of PD.
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http://dx.doi.org/10.1111/j.1469-1809.2011.00643.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077806PMC
May 2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

Nat Genet 2011 May 3;43(5):436-41. Epub 2011 Apr 3.

The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.
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http://dx.doi.org/10.1038/ng.801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090745PMC
May 2011

Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities.

PLoS Genet 2010 Sep 23;6(9):e1001130. Epub 2010 Sep 23.

Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold (alpha=1.03x10(-7)) were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, P=1.9x10(-36)). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (P=4.70x10(-8); Bonferroni-corrected P=0.022). Subsequent genotyping of SNPs in high linkage disequilibrium (r2>0.8) with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P=0.016; rs2073067, P=0.03; rs2072064, P=0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P=0.002 (P=1.90x10(-10) in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P=0.005; rs803422, P=0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development.
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http://dx.doi.org/10.1371/journal.pgen.1001130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944795PMC
September 2010

Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.

Arch Neurol 2010 Dec 9;67(12):1473-84. Epub 2010 Aug 9.

Department of Medicine, Boston University, USA.

Objectives: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes.

Design: Association study of AD and CLU, PICALM, CR1, and APOE genotypes.

Setting: Academic research institutions in the United States, Canada, and Israel.

Participants: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals.

Results: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE ε4, and an interaction term showed significant interaction between presence or absence of APOE ε4 and PICALM.

Conclusions: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.
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http://dx.doi.org/10.1001/archneurol.2010.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048805PMC
December 2010

Analysis of single nucleotide polymorphisms in the NOS2A gene and interaction with smoking in age-related macular degeneration.

Ann Hum Genet 2010 May 31;74(3):195-201. Epub 2010 Mar 31.

John P. Hussman Institute for Human Genomics and the Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Age-related macular degeneration (AMD) is a complex degenerative retinal disease influenced by both genetic and environmental risk factors. We assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk and modulate the effect of smoking in AMD. 998 Caucasian subjects (712 AMD cases and 286 controls) were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression models containing SNP genotypes, age, sex, smoking status and genotype/smoking interaction were constructed. SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI : 1.02, 1.65; P = 0.035). A significant interaction with smoking was detected at rs2248814 (P = 0.037). Stratified data by genotypes demonstrated that the association between AMD and smoking was stronger in carriers of AA genotypes (OR = 35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype (OR = 3.05; 95% CI: 1.36, 6.74) or GG genotype (OR = 2.1; 95% CI: 0.91, 4.84). The results suggest a possible synergistic interaction of AA genotype with smoking, although the result bears replication in larger samples. Our data suggests that SNPs in the NOS2A gene are associated with increased risk for AMD and might modulate the effect of smoking on AMD.
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http://dx.doi.org/10.1111/j.1469-1809.2010.00570.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882995PMC
May 2010