-
Manav Kapoor,
Jen-Chyong Wang,
Leah Wetherill,
Nhung Le, Sarah Bertelsen,
Anthony L Hinrichs,
John Budde,
Arpana Agrawal,
Kathleen Bucholz,
Danielle Dick, [......],
John I Nurnberger,
John Rice,
Nancy Saccone,
Marc Schuckit,
Jay Tischfield,
Bernice Porjesz,
Howard J Edenberg,
Laura Bierut,
Tatiana Foroud,
Alison Goate
[show abstract]
[hide abstract]
ABSTRACT: Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.
Human Genetics 06/2013; · 5.07 Impact Factor
-
Carlos Cruchaga,
John S K Kauwe,
Oscar Harari,
Sheng Chih Jin,
Yefei Cai,
Celeste M Karch,
Bruno A Benitez,
Amanda T Jeng,
Tara Skorupa,
David Carrell, [......],
Richard Mayeux,
Margaret A Pericak-Vance,
Lindsay A Farrer,
Gerard D Schellenberg,
Elaine R Peskind,
Douglas Galasko,
Anne M Fagan,
David M Holtzman,
John C Morris,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10(-9) for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10(-8) and p = 3.22 × 10(-9) for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10(-8) for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10(-4), 0.039, 4.86 × 10(-5), respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
Neuron 04/2013; · 14.74 Impact Factor
-
Manav Kapoor,
Jen-Chyong Wang,
Leah Wetherill,
Nhung Le, Sarah Bertelsen,
AnthonyL. Hinrichs,
John Budde,
Arpana Agrawal,
Kathleen Bucholz,
Danielle Dick, [......],
JohnI. Nurnberger Jr,
John Rice,
Nancy Saccone,
Marc Schuckit,
Jay Tischfield,
Bernice Porjesz,
HowardJ. Edenberg,
Laura Bierut,
Tatiana Foroud,
Alison Goate
[show abstract]
[hide abstract]
ABSTRACT: Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case–control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10−6) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10−7), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10−7) and PLCL1 genes (p = 4.1 × 10−6) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10−4) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10−3, 3 × 10−6), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.
Human Genetics 01/2013; · 5.07 Impact Factor
-
Carlos Cruchaga,
John S K Kauwe,
Petra Nowotny,
Kelly Bales,
Eve H Pickering,
Kevin Mayo, Sarah Bertelsen,
Anthony Hinrichs,
Anne M Fagan,
David M Holtzman,
John C Morris,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ(42) levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10(-13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ε4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10(-6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10(-9)).
Human Molecular Genetics 07/2012; 21(20):4558-4571. · 7.64 Impact Factor
-
Manav Kapoor,
Jen-Chyong Wang, Sarah Bertelsen,
Kathy Bucholz,
John P Budde,
Anthony Hinrichs,
Arpana Agrawal,
Andrew Brooks,
David Chorlian,
Danielle Dick, [......],
Niklas Manz,
John Nurnberger,
Bernice Porjesz,
John Rice,
Jay Tischfield,
Xiaoling Xuei,
Marc Schuckit,
Howard J Edenberg,
Laura J Bierut,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: Several genome-wide association and candidate gene studies have linked chromosome 15q24-q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28<r(2)<0.56) with variants that have previously been reported to affect risk for nicotine dependence and smoking related diseases in adults. The data suggests that an age-associated relationship underlies the association of SNPs in CHRNB4 with onset of chronic smoking behaviors in adolescents and young adults and may improve genetic information that will lead to better prevention and intervention for substance use disorders among adolescents and young adults.
PLoS ONE 01/2012; 7(3):e33513. · 4.09 Impact Factor
-
Carlos Cruchaga,
Petra Nowotny,
John S K Kauwe,
Perry G Ridge,
Kevin Mayo, Sarah Bertelsen,
Anthony Hinrichs,
Anne M Fagan,
David M Holtzman,
John C Morris,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene.
To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset.
We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue.
Alzheimer's Disease Research Center.
Research volunteers who were cognitively normal or had Alzheimer disease.
Disease status and age at onset.
We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or β-amyloid 42 levels or TOMM40 or APOE gene expression.
Although we did not replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.
Archives of neurology 08/2011; 68(8):1013-9. · 6.31 Impact Factor
-
Carlos Cruchaga,
Caroline Graff,
Huei-Hsin Chiang,
Jun Wang,
Anthony L Hinrichs,
Noah Spiegel, Sarah Bertelsen,
Kevin Mayo,
Joanne B Norton,
John C Morris,
Alison Goate
[show abstract]
[hide abstract]
ABSTRACT: To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association.
Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model.
Alzheimer's Disease Research Center. Subjects We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals.
Age at onset and GRN plasma levels.
The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622.
The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.
Archives of neurology 01/2011; 68(5):581-6. · 6.31 Impact Factor
-
Carlos Cruchaga,
John S K Kauwe,
Kevin Mayo,
Noah Spiegel, Sarah Bertelsen,
Petra Nowotny,
Aarti R Shah,
Richard Abraham,
Paul Hollingworth,
Denise Harold, [......],
Julie Williams,
Simon Lovestone,
Elaine R Peskind,
Ge Li,
James B Leverenz,
Douglas Galasko,
John C Morris,
Anne M Fagan,
David M Holtzman,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.
PLoS Genetics 09/2010; 6(9). · 8.69 Impact Factor
-
Laura J Bierut,
Arpana Agrawal,
Kathleen K Bucholz,
Kimberly F Doheny,
Cathy Laurie,
Elizabeth Pugh,
Sherri Fisher,
Louis Fox,
William Howells, Sarah Bertelsen, [......],
Bernice Porjesz,
Monika Ridinger,
Nancy L Saccone,
Scott F Saccone,
Marc A Schuckit,
Jay A Tischfield,
Jen C Wang,
Marcella Rietschel,
Alison M Goate,
John P Rice
[show abstract]
[hide abstract]
ABSTRACT: Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.
Proceedings of the National Academy of Sciences 03/2010; 107(11):5082-7. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease.
Journal of Alzheimer's disease: JAD 01/2010; 21(3):833-42. · 3.74 Impact Factor
-
Carlos Cruchaga,
John S. K. Kauwe,
Kevin Mayo,
Noah Spiegel, Sarah Bertelsen,
Petra Nowotny,
Aarti R. Shah,
Richard Abraham,
Paul Hollingworth,
Denise Harold, [......],
Simon Lovestone,
Elaine R. Peskind,
Ge Li,
James B. Leverenz,
Douglas Galasko,
John C. Morris,
Anne M. Fagan,
David M. Holtzman,
Alison M. Goate,
Initiative The Alzheimer's Disease Neuroimaging
[show abstract]
[hide abstract]
ABSTRACT: Author Summary
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 4.5 million people in the US. Genetic studies of AD have previously identified pathogenic mutations in three genes ( APP , PSEN1 and PSEN2 ) and polymorphisms in APOE as risk factors. These findings have led to a better understanding of the underlying disease mechanisms. However, half of all AD cases have no known genetic risk factors for disease. Most studies are designed to identify variants associated with risk or age at onset, but rarely cover other important facets of AD, such as disease progression or duration. In this study we have used an established AD biomarker (cerebrospinal fluid tau phosphorylated at threonine 181, ptau<sub>181</sub>) to find genetic variants that influence levels of ptau<sub>181</sub> in the cerebrospinal fluid. This novel and powerful approach has allowed us to identify a genetic factor located in the regulatory subunit of the calcineurin that is also strongly associated with rate of progression of AD. This study is important because it defines a strategy to find novel genetic factors influencing different facets of AD pathobiology including risk, onset and progression.
PLoS Genet. 01/2010; 6(9):e1001101.
-
Jen C Wang,
Carlos Cruchaga,
Nancy L Saccone, Sarah Bertelsen,
Pengyuan Liu,
John P Budde,
Weimin Duan,
Louis Fox,
Richard A Grucza,
Jason Kern, [......],
John Rice,
Scott F Saccone,
Noah Spiegel,
Joseph H Steinbach,
Jerry A Stitzel,
Marshall W Anderson,
Ming You,
Victoria L Stevens,
Laura J Bierut,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.
Human Molecular Genetics 06/2009; 18(16):3125-35. · 7.64 Impact Factor
-
Richard A Grucza,
Jen C Wang,
Jerry A Stitzel,
Anthony L Hinrichs,
Scott F Saccone,
Nancy L Saccone,
Kathleen K Bucholz,
C Robert Cloninger,
Rosalind J Neuman,
John P Budde, [......],
Jay Tischfield,
John I Nurnberger,
Laura Almasy,
Bernice Porjesz,
Samuel Kuperman,
Marc A Schuckit,
Howard J Edenberg,
John P Rice,
Alison M Goate,
Laura J Bierut
[show abstract]
[hide abstract]
ABSTRACT: A nonsynonymous coding polymorphism, rs16969968, of the CHRNA5 gene that encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence. The goal of this study was to examine the association of this variant with cocaine dependence.
Genetic association analysis was performed in two independent samples of unrelated case and control subjects: 1) 504 European Americans participating in the Family Study on Cocaine Dependence (FSCD) and 2) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholism (COGA).
In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (odds ratio = .67 per allele, p = .0045, assuming an additive genetic model), but in the reverse direction compared with that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD.
The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.
Biological psychiatry 12/2008; 64(11):922-9. · 8.93 Impact Factor
-
Laura Jean Bierut,
Jerry A Stitzel,
Jen C Wang,
Anthony L Hinrichs,
Richard A Grucza,
Xiaoling Xuei,
Nancy L Saccone,
Scott F Saccone, Sarah Bertelsen,
Louis Fox, [......],
John Nurnberger,
Ovide Pomerleau,
Bernice Porjesz,
Oliver Reyes,
Marc Schuckit,
Gary Swan,
Jay A Tischfield,
Howard J Edenberg,
John P Rice,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the alpha5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking.
Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function.
A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown.
This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.
American Journal of Psychiatry 09/2008; 165(9):1163-71. · 12.54 Impact Factor
-
John S K Kauwe,
Carlos Cruchaga,
Kevin Mayo,
Chiara Fenoglio, Sarah Bertelsen,
Petra Nowotny,
Daniela Galimberti,
Elio Scarpini,
John C Morris,
Anne M Fagan,
David M Holtzman,
Alison M Goate
[show abstract]
[hide abstract]
ABSTRACT: There is substantial evidence that cerebrospinal fluid (CSF) levels of both Abeta42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Abeta and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Abeta42 levels were used to stratify the sample into those with and without likely Abeta deposition in the brain the association was only observed in individuals with evidence of Abeta deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Abeta deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (Abeta deposition) interaction that places changes in CSF tau after Abeta deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.
Proceedings of the National Academy of Sciences 07/2008; 105(23):8050-4. · 9.68 Impact Factor
-
Danielle M Dick,
Fazil Aliev,
Jen C Wang,
Scott Saccone,
Anthony Hinrichs, Sarah Bertelsen,
John Budde,
Nancy Saccone,
Tatiana Foroud,
John Nurnberger, [......],
Raymond Crowe,
Samuel Kuperman,
John Kramer,
Jay A Tischfield,
Victor Hesselbrock,
Howard J Edenberg,
Bernice Porjesz,
John P Rice,
Laura Bierut,
Alison Goate
[show abstract]
[hide abstract]
ABSTRACT: Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. With a sample of 262 densely affected families, a peak logarithm of odds (LOD) score for alcohol dependence of 2.9 was observed at D7S1799. The LOD score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14). To follow up on this linkage region, we systematically screened single nucleotide polymorphisms (SNPs) across a 2 LOD support interval surrounding the alcohol dependence peak.
The SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. Across the 18-Mb region, genotyped by the Center for Inherited Disease Research (CIDR), 1340 SNPs were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families.
Eight SNPs showed association with alcohol dependence at p < .01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence.
These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate.
Biological psychiatry 06/2008; 63(11):1047-53. · 8.93 Impact Factor
-
Danielle M Dick,
Fazil Aliev,
Jen C Wang,
Richard A Grucza,
Marc Schuckit,
Samuel Kuperman,
John Kramer,
Anthony Hinrichs, Sarah Bertelsen,
John P Budde,
Victor Hesselbrock,
Bernice Porjesz,
Howard J Edenberg,
Laura Jean Bierut,
Alison Goate
[show abstract]
[hide abstract]
ABSTRACT: Twin studies provide compelling evidence that alcohol and drug dependence, childhood conduct disorder, adult antisocial behavior, and disinhibitory personality traits share an underlying genetic liability that contributes to a spectrum of externalizing behaviors. However, this information has not been widely used in gene identification efforts, which have focused on specific disorders diagnosed using traditional psychiatric classification systems.
To test the utility of using a multivariate externalizing phenotype in (1) linkage analyses and (2) association analyses to identify genes that contribute broadly to a spectrum of externalizing disorders.
Data were analyzed from the Collaborative Study on the Genetics of Alcoholism. Linkage analyses were conducted using data from a genome-wide 10-cM microsatellite scan. Association analyses were conducted on 27 single-nucleotide polymorphisms genotyped across a candidate gene, the muscarinic acetylcholine receptor M2 gene (CHRM2).
Six centers across the United States.
Approximately 2300 individuals from 262 families.
Lifetime symptom counts of alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder and novelty seeking, sensation seeking, and general externalizing component scores consisting of a composite of the previous 6 variables.
Principal component analyses indicated that the 6 individual variables loaded on a single externalizing factor. Linkage analyses using the resultant component scores identified a region on chromosome 7 consistent with a gene that broadly predisposes individuals to externalizing behavior. Association analyses of a candidate gene, CHRM2, previously of interest in the Collaborative Study on the Genetics of Alcoholism, suggest that it is involved in a general externalizing phenotype.
Broader conceptualizations of psychiatric disorders, such as studying a spectrum of externalizing psychopathology, may aid in identifying susceptibility genes and understanding the pathways through which genetic factors affect vulnerability for a variety of poor outcomes.
Archives of general psychiatry 04/2008; 65(3):310-8. · 12.26 Impact Factor
-
Arpana Agrawal,
Anthony L Hinrichs,
Gerald Dunn, Sarah Bertelsen,
Danielle M Dick,
Scott F Saccone,
Nancy L Saccone,
Richard A Grucza,
Jen C Wang,
C Robert Cloninger, [......],
Tatiana Foroud,
Victor Hesselbrock,
John Kramer,
Kathleen K Bucholz,
Samuel Kuperman,
John I Nurnberger,
Bernice Porjesz,
Marc A Schuckit,
Alison M Goate,
Laura J Bierut
[show abstract]
[hide abstract]
ABSTRACT: Dependence on alcohol and illicit drugs frequently co-occur. Results from a number of twin studies suggest that heritable influences on alcohol dependence and drug dependence may substantially overlap. Using large, genetically informative pedigrees from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed quantitative linkage analyses using a panel of 1717 SNPs. Genome-wide linkage analyses were conducted for quantitative measures of DSM-IV alcohol dependence criteria, cannabis dependence criteria and dependence criteria across any illicit drug (including cannabis) individually and in combination as an average score across alcohol and illicit drug dependence criteria. For alcohol dependence, LOD scores exceeding 2.0 were noted on chromosome 1 (2.0 at 213 cM), 2 (3.4 at 234 cM) and 10 (3.7 at 60 cM). For cannabis dependence, a maximum LOD of 1.9 was noted at 95 cM on chromosome 14. For any illicit drug dependence, LODs of 2.0 and 2.4 were observed on chromosome 10 (116 cM) and 13 (64 cM) respectively. Finally, the combined alcohol and/or drug dependence symptoms yielded LODs >2.0 on chromosome 2 (3.2, 234 cM), 10 (2.4 and 2.6 at 60 cM and 116 cM) and 13 (2.1 at 64 cM). These regions may harbor genes that contribute to the biological basis of alcohol and drug dependence.
Drug and Alcohol Dependence 02/2008; 93(1-2):12-20. · 3.38 Impact Factor
-
Danielle M Dick,
Jen C Wang,
Jevon Plunkett,
Fazil Aliev,
Anthony Hinrichs, Sarah Bertelsen,
John P Budde,
Elianna L Goldstein,
Daniel Kaplan,
Howard J Edenberg,
John Nurnberger,
Victor Hesselbrock,
Marc Schuckit,
Sam Kuperman,
Jay Tischfield,
Bernice Porjesz,
Henri Begleiter,
Laura Jean Bierut,
Alison Goate
[show abstract]
[hide abstract]
ABSTRACT: There is an extensive and inconsistent literature on the association of the dopamine D2 receptor gene (DRD2) with alcohol dependence. Conflicting results have been attributed to differences in the severity of the alcohol dependence phenotype across studies, failure to exclude related disorders from comparison groups, and artifacts of population-stratification. Recently the genetic polymorphism most widely analyzed in DRD2, Taq1A, has been discovered to reside in a neighboring gene, ankyrin repeat and kinase domain containing 1 (ANKK1), located 10 kb downstream from DRD2.
To more carefully characterize evidence for association across this region, we genotyped 26 single nucleotide polymorphisms (SNPs) spanning DRD2 and ANKK1 in a sample of 219 Caucasian families (n = 1,923) from the Collaborative Study on the Genetics of Alcoholism (COGA), making this the most extensive analysis to date of association between this region and alcohol dependence. We used family-based analyses robust to population-stratification, and we made use of rich phenotypic data to analyze alcohol dependence and subtypes hypothesized in the literature to be more directly influenced by DRD2.
We found that the evidence for association is strongest in the 5' linkage disequilibrium block of ANKK1 (that does not contain Taq1A), with weak evidence of association with a small number of SNPs in DRD2. The association in ANKK1 is strongest among the subsets of alcoholics with medical complications and with antisocial personality disorder.
More extensive genotyping across DRD2 and ANKK1 suggests that the association with alcohol dependence observed in this region may be due to genetic variants in the ANKK1 gene. ANKK1 is involved in signal transduction pathways and is a plausible biological candidate for involvement in addictive disorders.
Alcoholism Clinical and Experimental Research 11/2007; 31(10):1645-53. · 3.34 Impact Factor
-
Danielle M Dick,
Arpana Agrawal,
Jen C Wang,
Anthony Hinrichs, Sarah Bertelsen,
Kathleen K Bucholz,
Marc Schuckit,
John Kramer,
John Nurnberger,
Jay Tischfield,
Howard J Edenberg,
Alison Goate,
Laura J Bierut
[show abstract]
[hide abstract]
ABSTRACT: Twin data suggest that alcohol dependence comorbid with illicit drug dependence represents a more heritable form of the disorder. In the Collaborative Study on the Genetics of Alcoholism sample, approximately half the alcohol-dependent individuals also meet diagnostic criteria for illicit drug dependence. In this study, we tested for heterogeneity in the association between the muscarinic acetylcholine M2 receptor gene (CHRM2) and alcohol dependence, reported previously in the full sample, among the subgroups of alcohol-dependent individuals with and without comorbid drug dependence.
Family-based association tests were conducted separately (a) in individuals with alcohol dependence with comorbid drug dependence (n = 477) and (b) in individuals with alcohol dependence without comorbid drug dependence (n = 433). These subgroups were subsequently compared on other phenotypic characteristics.
The evidence for association between CHRM2 and alcohol dependence came entirely from the subgroup of individuals with comorbid drug dependence. There was no evidence of association with CHRM2 among the alcohol-dependent individuals without drug dependence. Subsequent phenotypic analyses suggest that the subgroup of alcohol-dependent individuals with comorbid drug dependence differ on a number of other phenotypic characteristics, including several measures of the severity of their alcohol problems, personality traits and comorbid psychiatric disorders.
These analyses provide specific genetic evidence suggesting that alcohol dependence with comorbid drug dependence represents a particularly severe form of the disorder, with higher genetic contribution to vulnerability.
Addiction 08/2007; 102(7):1131-9. · 4.31 Impact Factor
