Publications by authors named "Jürg Ott"

155 Publications

Polymorphisms in Stress-Related Genes Are Associated with Reduced Cocaine Abuse and Longer Retention in Methadone Maintenance Treatment for Opioid Use Disorder.

Eur Addict Res 2020 Nov 26:1-8. Epub 2020 Nov 26.

Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background: As CRH-binding protein (CRHBP) SNP rs1500 was associated with reduced cocaine abuse after 1 year in methadone maintenance treatment (MMT) for heroin addiction, we evaluated the association of additional 28 selected SNPs, in 17 stress-related genes, with MMT outcome.

Methods: The distribution of genotypes of each SNP by cocaine abuse after 1 year in MMT was assessed under the dominant and recessive models using χ2. Cumulative retention (up to 26.5 years) was studied using Kaplan-Meier analyses. Logistic regression and Cox model were used for multivariate analyses.

Results: Of a nonselective sample of 404 patients, 25 patients with <50% Europeans/Middle Eastern ancestry were excluded. Of the remaining 379 patients, 330 (87.1%) stayed at least 1 year in treatment. Four SNPs were associated with cocaine abuse after 1 year in MMT. A lower proportion of cocaine abusers was found in the groups of subjects with the following genotypes: arginine vasopressin (AVP) SNP rs2282018 CC, CRHBP rs7728378 TT, galanin rs3136541 TT/TC, and neuropeptide Y receptor Y1 (NPY1R) rs4518200 AA. The following independent variables were associated with lack of cocaine in urine after 1 year (multivariate analyses): CRHBP rs7728378 TT, NPY1R rs4518200 AA, no cocaine in urine on admission, as well as opiate and benzodiazepine use after 1 year in MMT. Cumulative retention (n = 379) was longer in carriers of AVP rs2282018 CC (13.7 years, 95% CI 11.1-16.2) versus TT/TC genotypes (10.5, 95% CI 9.4-11.5) (p = 0.0230) Conclusions: The study suggests that a reduction in cocaine abuse and longer retention among MMT patients is mediated in part by variants in stress-related genes and is a step toward precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511898DOI Listing
November 2020

A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q.

Z Kinder Jugendpsychiatr Psychother 2020 Nov;48(6):478-489

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany.

Developmental dyslexia is a highly heritable specific reading and writing disability. To identify a possible new locus and candidate gene for this disability, we investigated a four-generation pedigree where transmission of dyslexia is consistent with an autosomal dominant inheritance pattern. We performed genome wide array-based SNP genotyping and parametric linkage analysis and sequencing analysis of protein-coding exons, exon-intron boundaries and conserved extragenic regions within the haplotype cosegregating with dyslexia in DNA from one affected and one unaffected family member. Cosegregation was confirmed by sequencing all available family members. Additionally, we analyzed 96 dyslexic individuals who had previously shown positive LOD scores on chromosome 4q28 as well as an even larger sample ( = 2591). We found a single prominent linkage interval on chromosome 4q, where sequence analysis revealed a nucleotide variant in the 3' UTR of brain expressed in the dyslexic family member that cosegregated with dyslexia. This sequence alteration might affect the binding efficiency of the IGF2BP1 RNA-binding protein and thus influence the expression level of the gene product. An analysis of 96 individuals from a cohort of dyslexic individuals revealed a second heterozygous variant in this gene, which was absent in the unaffected sister of the proband. An investigation of the region in a much larger sample further found a nominal -value of 0.0016 for verbal short-term memory (digit span) in 2,591 individuals for a neighboring SNV. After correcting for the local number of analyzed SNVs, and after taking into account linkage disequilibrium, we found this corresponds to a -value of 0.0678 for this phenotype. We describe a new locus for familial dyslexia and discuss the possibility that might play a role in the etiology of a monogenic form of dyslexia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1024/1422-4917/a000758DOI Listing
November 2020

Variants of opioid genes and response to treatment of opioid use disorder with buprenorphine-naloxone versus extended-release naltrexone in Caucasians.

Am J Drug Alcohol Abuse 2020 11 27;46(6):761-768. Epub 2020 Aug 27.

Laboratory of the Biology of Addictive Diseases, the Rockefeller University , New York, NY, USA.

: Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/ kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse. : Determine whether gene variants in the opioid gene system are associated with better or worse treatment response. : In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the National Drug Abuse Clinical Trials Network, DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians ( = 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to model each outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction. : There were no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions. : The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00952990.2020.1797064DOI Listing
November 2020

Further evidence for the association of ,  and  variants with opioid dependence.

Pharmacogenomics 2020 08 6;21(13):903-917. Epub 2020 Aug 6.

Laboratory of The Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

Heroin addiction is a chronic, relapsing disease that has genetic and environmental, including drug-induced, contributions. Stress influences the development of addictions. This study was conducted to determine if variants in stress-related genes are associated with opioid dependence (OD). One hundred and twenty variants in 26 genes were analyzed in 597 Dutch subjects. Patients included 281 OD in methadone maintenance with or without heroin-assisted treatment and 316 controls. Twelve SNPs in seven genes showed a nominally significant association with OD. Experiment-wise significant associations (p < 0.05) were found for three SNP pairs, through an interaction effect: / rs4691910/rs1893679, / rs4691910/rs3136541 and rs9807208/rs3136541. This study lends more evidence to previous reports of association of stress-related variants with heroin dependence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2020-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487975PMC
August 2020

Population genetics: past, present, and future.

Hum Genet 2021 Feb 18;140(2):231-240. Epub 2020 Jul 18.

Laboratory of Statistical Genetics, Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.

We present selected topics of population genetics and molecular phylogeny. As several excellent review articles have been published and generally focus on European and American scientists, here, we emphasize contributions by Japanese researchers. Our review may also be seen as a belated 50-year celebration of Motoo Kimura's early seminal paper on the molecular clock, published in 1968.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02208-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368598PMC
February 2021

Shared genomic segment analysis with equivalence testing.

Genet Epidemiol 2020 Oct 16;44(7):741-747. Epub 2020 Jul 16.

Department of Statistical Genetics, Laboratory of Statistical Genetics, Rockefeller University, New York, New York.

An important aspect of disease gene mapping is replication, that is, a putative finding in one group of individuals is confirmed in another set of individuals. As it can happen by chance that individuals share an estimated disease position, we developed a statistical approach to determine the p-value for multiple individuals or families to share a possibly small number of candidate susceptibility variants. Here, we focus on candidate variants for dominant traits that have been obtained by our previously developed heterozygosity analysis, and we are testing the sharing of candidate variants obtained for different individuals. Our approach allows for multiple pathogenic variants in a gene to contribute to disease, and for estimated disease variant positions to be imprecise. Statistically, the method developed here falls into the category of equivalence testing, where the classical null and alternative hypotheses of homogeneity and heterogeneity are reversed. The null hypothesis situation is created by permuting genomic locations of variants for one individual after another. We applied our methodology to the ALSPAC data set of 1,927 whole-genome sequenced individuals, where some individuals carry a pathogenic variant for the BRCA1 gene, but no two individuals carry the same variant. Our shared genomic segment analysis found significant evidence for BRCA1 pathogenic variants within ±5 kb of a given DNA variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540579PMC
October 2020

Maximal Segmental Score Method for Localizing Recessive Disease Variants Based on Sequence Data.

Front Genet 2020 12;11:555. Epub 2020 Jun 12.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Background: Due to the affordability of whole-genome sequencing, the genetic association design can now address rare diseases. However, some common statistical association methods only consider homozygosity mapping and need several criteria, such as sliding windows of a given size and statistical significance threshold setting, such as -value < 0.05 to achieve good power in rare disease association detection.

Methods: Our region-specific method, called expanded maximal segmental score (eMSS), converts -values into continuous scores based on the maximal segmental score (MSS) (Lin et al., 2014) for detecting disease-associated segments. Our eMSS considers the whole genome sequence data, not only regions of homozygosity in candidate genes. Unlike sliding window methods of a given size, eMSS does not need predetermined parameters, such as window size or minimum or maximum number of SNPs in a segment. The performance of eMSS was evaluated by simulations and real data analysis for autosomal recessive diseases multiple intestinal atresia (MIA) and osteogenesis imperfecta (OI), where the number of cases is extremely small. For the real data, the results by eMSS were compared with a state-of-the-art method, HDR-del (Imai et al., 2016).

Results: Our simulation results show that eMSS had higher power as the number of non-causal haplotype blocks decreased. The type I error for eMSS under different scenarios was well controlled, < 0.05. For our observed data, the bone morphogenetic protein 1 () gene on chromosome 8, the Violaxanthin de-epoxidase-related chloroplast () gene on chromosome 12 associated with OI, and the tetratricopeptide repeat domain 7A () gene on chromosome 2 associated with MIA have previously been identified as harboring the relevant pathogenic mutations.

Conclusions: When compared to HDR-del, our eMSS is powerful in analyzing even small numbers of recessive cases, and the results show that the method can further reduce numbers of candidate variants to a very small set of susceptibility pathogenic variants underlying OI and MIA. When we conduct whole-genome sequence analysis, eMSS used 3/5 the computation time of HDR-del. Without additional parameters needing to be set in the segment detection, the computational burden for eMSS is lower compared with that in other region-specific approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325894PMC
June 2020

A 3' UTR SNP rs885863, a cis-eQTL for the circadian gene VIPR2 and lincRNA 689, is associated with opioid addiction.

PLoS One 2019 5;14(11):e0224399. Epub 2019 Nov 5.

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York, United States of America.

There is a reciprocal relationship between the circadian and the reward systems. Polymorphisms in several circadian rhythm-related (clock) genes were associated with drug addiction. This study aims to search for associations between 895 variants in 39 circadian rhythm-related genes and opioid addiction (OUD). Genotyping was performed with the Smokescreen® array. Ancestry was verified by principal/MDS component analysis and the sample was limited to European Americans (EA) (OUD; n = 435, controls; n = 138). Nominally significant associations (p < 0.01) were detected for several variants in genes encoding vasoactive intestinal peptide receptor 2 (VIPR2), period circadian regulator 2 (PER2), casein kinase 1 epsilon (CSNK1E), and activator of transcription and developmental regulator (AUTS2), but no signal survived correction for multiple testing. There was intriguing association signal for the untranslated region (3' UTR) variant rs885863 in VIPR2, (p = .0065; OR = 0.51; 95% CI 0.31-0.51). The result was corroborated in an independent EA OUD sample (n = 398, p = 0.0036; for the combined samples). Notably, this SNP is an expression quantitative trait locus (cis-eQTL) for VIPR2 and a long intergenic non-coding RNA, lincRNA 689, in a tissue-specific manner, based on the Genotype-Tissue Expression (GTEx) project. Vasoactive intestinal peptide (VIP) is an important peptide of light-activated suprachiasmatic nucleus cells. It regulates diverse physiological processes including circadian rhythms, learning and memory, and stress response. This is the first report of an association of a VIPR2 variant and OUD. Additionally, analysis of combinations of single nucleotide polymorphisms (SNPs) genotypes revealed an association of PER2 SNP rs80136044, and SNP rs4128839, located 41.6 kb downstream of neuropeptide Y receptor type 1 gene, NPY1R (p = 3.4 × 10-6, OR = 11.4, 95% CI 2.7-48.2). The study provides preliminary insight into the relationship between genetic variants in circadian rhythm genes and long non-coding RNA (lncRNAs) in their vicinity, and opioid addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830932PMC
April 2020

Are trait impulsivity and exposure to cannabis or alcohol associated with the age of trajectory of cocaine use? A gender-specific dimensional analysis in humans with cocaine dependence diagnosis.

Exp Clin Psychopharmacol 2020 Jun 19;28(3):317-327. Epub 2019 Aug 19.

Laboratory of the Biology of Addictive Diseases.

Cocaine use disorders (CUD) cause major morbidity and optimized prevention efforts are critical. It is unclear if trait impulsivity and exposure to cannabis or alcohol are associated with age trajectory of cocaine use (e.g., age of onset of heaviest use, or time of escalation), or with vulnerability to develop a CUD. This is an observational study with volunteers (≥ 18 years old), from a metropolitan area. The sample ( = 1,010) included: = 360 normal volunteers, = 438 with cocaine dependence (CD) diagnoses, and = 212 with other addictive diseases. Trait impulsivity was examined with BIS-11 scores. Maximal self-exposure to cannabis, alcohol, and cocaine were characterized dimensionally with Kreek-McHugh-Schluger-Kellogg (KMSK) scales. Time of escalation was defined as the interval between age of first use and age of onset of heaviest use. Onset of maximal use of cannabis (median age = 17) and alcohol (median age = 21) preceded that of cocaine (median age = 27), in volunteers with CD. Multivariate Cox regressions in volunteers with CD show that increasing self-exposure to cannabis was a predictor of earlier onset of heaviest use of cocaine. Also, more rapid time of escalation of alcohol was a predictor of more rapid time of escalation of cocaine. A multiple logistic regression shows that increasing self-exposure to cannabis or alcohol was a positive predictor of odds of CD diagnosis. Trait impulsivity and gender were not significant predictors in these multivariate analyses. This study shows that aspects of adolescent exposure to nonmedical cannabis and alcohol are predictors of early onset of CUD, and may be potentially targeted for prevention efforts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/pha0000314DOI Listing
June 2020

Heterozygosity mapping for human dominant trait variants.

Hum Mutat 2019 07 24;40(7):996-1004. Epub 2019 Apr 24.

Laboratory of Statistical Genetics, Rockefeller University, New York, New York.

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617796PMC
July 2019

VMAT2 gene () variants associated with a greater risk for developing opioid dependence.

Pharmacogenomics 2019 04 15;20(5):331-341. Epub 2019 Apr 15.

Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

To determine if selected serotonergic and noradrenergic gene variants are associated with heroin addiction. A total of 126 variants in 19 genes in subjects with Dutch European ancestry from The Netherlands. Subjects included 281 opioid-dependent volunteers in methadone maintenance or heroin-assisted treatment, 163 opioid-exposed but not opioid-dependent volunteers who have been using illicit opioids but never became opioid-dependent and 153 healthy controls. Nominal associations were indicated for 20 variants in six genes including an experiment-wise significant association from the combined effect of three SNPs (rs363332, rs363334 and rs363338) with heroin dependence (p = 0.047). Further studies are warranted to confirm and elucidate the role of these variants in the vulnerability to opioid addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2018-0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566135PMC
April 2019

Association of variants of prodynorphin promoter 68-bp repeats in caucasians with opioid dependence diagnosis: Effect on age trajectory of heroin use.

Neurosci Lett 2019 06 29;704:100-105. Epub 2019 Mar 29.

Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Ave, New York, NY, 10065, USA.

The dynorphin/kappa opioid receptor (Dyn/KOR) system is involved in reward processing and dysphoria/anhedonia. Exposure to mu-opioid receptor agonists such as heroin increases expression of the prodynorphin gene (PDYN) in the brain. In this study in a Caucasian cohort, we examined the association of the functional PDYN 68-bp repeat polymorphism with opioid use disorders. In this case-control study, 554 subjects with Caucasian ancestry (142 healthy controls, 153 opioid-exposed, but never opioid dependent, NOD, and 259 with an opioid dependence diagnosis, OD) were examined for association of the PDYN 68-bp repeats with the diagnosis of opioid dependence (DSM-IV criteria), with a dimensional measure of heroin exposure (KMSK scale), and age trajectory parameters of heroin use (age of heroin first use, and age of onset of heaviest use). The PDYN 68-bp repeat genotype (classified as: "short-short" [SS], "long-long" [LL], and "short-long" [SL], based on the number of repeats) was not associated with categorical opioid dependence diagnoses. However, the LL genotype was associated with later age of first heroin use than the SS + SL genotype (19 versus 18 years; p < 0.01). This was also confirmed by a significant positive correlation between the number of repeats and the age of first use of heroin, in volunteers with OD (Spearman r = 0.16; p = 0.01). This suggests that the functional PDYN 68-bp repeat genotype is associated with the age of first use of heroin in Caucasians diagnosed with opioid dependence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2019.03.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594859PMC
June 2019

Genetic Variant in the CRH-binding Protein Gene (CRHBP) is Associated With Cessation of Cocaine Use in Methadone Maintenance Patients With Opioid Addiction.

J Addict Med 2019 Nov/Dec;13(6):430-435

Dr Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Tel Aviv Sourasky Medical Center (EP, MA); Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel (EP); The Laboratory of the Biology of Addictive Diseases (OL, MR, MJK, MA); The Laboratory of Statistical Genetics, The Rockefeller University, New York, NY (JO); Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Las Vegas, NV (MA).

Objectives: We have previously shown associations between 4 genetic variants in opioid and stress-related genes (OPRM1, NPYR1/NPYR5, NR3C1, and CRHBP) and prolonged abstinence from heroin without methadone maintenance treatment (MMT). We currently assessed the associations between these variants and MMT patients' characteristics.

Methods: A non-selective group of 351 patients who stayed at least 1 year in their first admission to MMT were genotyped and their characteristics and substance in urine on admission and after 1 year were studied.

Results: The proportions of patients with both cocaine and benzodiazepine abuse were reduced significantly after 1 year in MMT; however, cocaine abuse cessation was significantly associated with the non-carriers of the CRHBP (corticotrophin releasing hormone binding protein) SNP rs1500 minor C allele (GG genotype) (P = 0.0009, PBonferroni = 0.0221). More carriers of the 2 C alleles (CC genotype) than carriers of the GC and GG genotypes abused cocaine on admission (32.3% vs 19.7%, respectively, P = 0.0414, recessive model), and more of the C allele carriers (GC and CC genotypes) than non-carriers (GG genotype) abused cocaine after 1 year in MMT (25.7% vs 15.8%, respectively, P = 0.0334, dominant model). Abusers of benzodiazepine were more prevalent among carriers of the C allele compared with non-carriers on admission (60.6% vs 45.9%, respectively, P = 0.0080, dominant model), as well as after 1 year in MMT (50.9% vs 39.1%, respectively, P = 0.0362).

Conclusions: Reduction in cocaine abuse among MMT patients may be mediated by a genetic effect in a stress-related gene (CRHBP SNP rs1500 minor C allele). Evaluations of larger samples, additional SNPs, and different populations are needed to support these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ADM.0000000000000515DOI Listing
July 2020

A novel association of rs13334070 in the RPGRIP1L gene with adiposity factors discovered by joint linkage and linkage disequilibrium analysis in Iranian pedigrees: Tehran Cardiometabolic Genetic Study (TCGS).

Genet Epidemiol 2019 04 30;43(3):342-351. Epub 2018 Dec 30.

Department of Cellular and Molecular, Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Understanding the genetic and metabolic bases of obesity is helpful in planning and developing health strategies. Therefore, the first family-based joint linkage and linkage disequilibrium study was conducted in Iranian pedigrees to assess the relationship between obesity and single-nucleotide polymorphisms (SNPs) located in the 16q12.2 region. In the present study, a total of 13,344 individuals were included, of whom 12,502 individuals were within 3,109 pedigrees and 842 were unrelated singletons. To investigate the relationship between obesity and genetic variants, a joint model of linkage and linkage disequilibrium was applied. Moreover, a sequence kernel association test (SKAT) was used to evaluate the association of the SNP set with body size and lipid profile measurements. The joint model showed that rs13334070, in the intron 4 of the RPGRIP1L gene, has a significant association with obesity. According to the 4-gamete rule, which is a procedure for constructing SNP sets by considering recombination occurrence between SNPs, this polymorphism has a high correlation with six nearby SNPs that make an SNP set. SKAT showed that this SNP set has a significant association with body size factors, but almost no association with most of the lipid profile measurements. In conclusion, from the result of this study, it might be reasonable to consider RPGRIP1L as an important gene whose variations could be associated with obesity risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22179DOI Listing
April 2019

Re-evaluation of the KMSK scales, rapid dimensional measures of self-exposure to specific drugs: Gender-specific features.

Drug Alcohol Depend 2018 09 21;190:179-187. Epub 2018 Jul 21.

Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.

Background: The Kreek-McHugh-Schluger-Kellogg (KMSK) scales provide a rapid assessment of maximal self-exposure to specific drugs and can be used as a dimensional instrument. This study provides a re-evaluation of the KMSK scales for cannabis, alcohol, cocaine, and heroin in a relatively large multi-ethnic cohort, and also the first systematic comparison of gender-specific profiles of drug exposure with this scale.

Methods: This was an observational study of n = 1,133 consecutively ascertained adult volunteers. The main instruments used were the SCID-I interview (DSM-IV criteria) and KMSK scales for cannabis, alcohol, cocaine, and heroin.

Results: Participants were 852 volunteers (297 female) with specific DSM-IV abuse or dependence diagnoses, and 281 volunteers without any drug diagnoses (154 female). Receiver operating characteristic (ROC) curves were calculated for concurrent validity of KMSK scores with the respective DSM-IV dependence diagnoses. The areas under the ROC curves for men and women combined were 99.5% for heroin, 97% for cocaine, 93% for alcohol, and 85% for cannabis. Newly determined optimal KMSK "cutpoint" scores were identical for men and women for cocaine and heroin dependence diagnoses, but were higher in men than in women, for cannabis and alcohol dependence diagnoses.

Conclusions: This study confirms the scales' effectiveness in performing rapid dimensional analyses for cannabis, alcohol, cocaine, and heroin exposure, in a cohort larger than previously reported, with "cutpoints" changed from initial determinations, based on this larger sample. The KMSK scales also detected gender differences in self-exposure to alcohol and cannabis that are associated with the respective dependence diagnoses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drugalcdep.2018.05.028DOI Listing
September 2018

The combined effects of cardiovascular disease related SNPs on ischemic stroke.

J Neurol Sci 2018 05 6;388:141-145. Epub 2018 Mar 6.

Beijing Hypertension League Institute, No.24, Shijingshan Road, Beijing 100043, China. Electronic address:

Purpose: Previous studies have revealed multiple common variants associated with known risk factors for cardiovascular disease (CVD). Ischemic stroke (IS) and CVD share several risk factors with each having substantial heritability. We aimed to generate a multi-locus genetic risk score (GRS) for IS based on CVD related SNPs to evaluate their combined effects on IS.

Methods: A total of 851 patients and 977 controls were selected from Beijing, Tianjin, Shandong, Shanxi, Shaanxi and Heilongjiang communities. The candidate genes were genotyped by PCR-hybridization. Information about demographic factors, history of disease (such as hypertension), and lifestyle was obtained using structured questionnaires. A GRS model weighted by the absolute value of regression coefficient β was established to comprehensively assess the association between candidate SNPs and IS. Using the area under the receiver operating characteristic curve (AUC) to evaluate the value of GRS on predicting IS.

Results: The GRS of cases was 2.87 ± 0.28, which was significantly higher than controls' GRS (2.78 ± 0.30) (P < 0.000). With the increase of the GRS, the risk of IS became higher (P < 0.000). Subjects in the top quartile of the GRS had about 1.9-fold increased risk of IS compared with subjects in the lowest quartile (OR  = 1.880, 95%CI = 1.442-2.452, P < 0.000). The AUC = 0.580, P < 0.000.

Conclusion: 13 CVD related SNPs had combined effects on IS. The GRS of cases was significantly higher than controls' GRS. As the GRS increased, the risk of IS increased. The GRS model has some value for the prediction of IS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2018.03.013DOI Listing
May 2018

Dopamine gene variants in opioid addiction: comparison of dependent patients, nondependent users and healthy controls.

Pharmacogenomics 2018 Jan 6;19(2):95-104. Epub 2017 Dec 6.

Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Ave, New York, NY 10065, USA.

Aim: To determine whether specific dopaminergic system gene variants are associated with opioid dependence.

Patients & Methods: Subjects included 153 healthy controls, 163 opioid exposed, but not dependent and 281 opioid dependent. Genotypes of 90 variants in 13 genes were examined.

Results: The most significant results were obtained for DA β-hydroxylase variants, rs2073837 and rs1611131, which were associated with protection from addiction (q = 0.0172, 0.0415, respectively) and the functional TH variant, rs2070762, was associated with more risk (q = 0.0387). The three variants also showed a combined effect that remained significant after correction for multiple testing (p = 0.0039).

Conclusion: These data offer support that dopaminergic gene variants have a role in opioid dependence and warrant further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2017-0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826863PMC
January 2018

HDR-del: A tool based on Hamming distance for prioritizing pathogenic chromosomal deletions in exome sequencing.

Hum Mutat 2017 12 21;38(12):1796-1800. Epub 2017 Sep 21.

Laboratory of Statistical Genetics, Rockefeller University, New York.

High-density oligonucleotide arrays have widely been used to detect pathogenic chromosomal deletions. In addition to high-density oligonucleotide arrays, programs using whole-exome sequencing have become available for estimating copy-number variations using depth of coverage. Here, we propose a new statistical method, HDR-del, to prioritize pathogenic chromosomal deletions based on Hamming distance in exome sequencing. In vcf (variant call format) files generated from exome sequencing, hemizygous chromosomal deletion regions lack heterozygous variants and lead to apparent long runs of homozygosity (ROH). In our Hamming distance ratio (HDR)-del approach, we calculate the "difference" in heterozygous status between an affected individual and control individuals using the HDR over all candidate chromosomal deletion regions defined as ROH longer than 1Mbp. Using a suitable test statistic, which is expected to be large for a true pathogenic deletion region, we prioritize candidate chromosomal deletion regions based on this statistic. In our approach, we were able to considerably narrow down true pathogenic chromosomal deletion regions, which were confirmed by high-density oligonucleotide arrays in four mitochondrial disease patients. Our HDR-del approach represents an easy method for detecting chromosomal deletions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23298DOI Listing
December 2017

To aggregate or not, that is the question. A commentary on single-nucleotide variant proportion in genes: a new concept to explore major depression based on DNA sequencing data.

Authors:
Jurg Ott

J Hum Genet 2017 Apr 2;62(5):523. Epub 2017 Feb 2.

Laboratory of Statistical Genetics, Rockefeller University, New York, NY, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jhg.2017.7DOI Listing
April 2017

Variants of opioid system genes are associated with non-dependent opioid use and heroin dependence.

Drug Alcohol Depend 2016 Nov 5;168:164-169. Epub 2016 Sep 5.

Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

Background: Heroin addiction is a chronic, relapsing brain disease. Genetic factors are involved in the development of drug addiction. The aim of this study was to determine whether specific variants in genes of the opioid system are associated with non-dependent opioid use and heroin dependence.

Methods: Genetic information from four subject groups was collected: non-dependent opioid users (NOD) [n=163]; opioid-dependent (OD) patients in methadone maintenance treatment (MMT) [n=143]; opioid-dependent MMT-resistant patients in heroin-assisted treatment (HAT) [n=138]; and healthy controls with no history of opioid use (HC) [n=153]. Eighty-two variants in eight opioid system genes were studied. To establish the role of these genes in (a) non-dependent opioid use, and (b) heroin dependence, the following groups were compared: HC vs. NOD; HC vs. OD (MMT+HAT); and NOD vs. OD (MMT+HAT).

Results: Five unique SNPs in four genes showed nominally significant associations with non-dependent opioid use and heroin dependence. The association of the delta opioid receptor (OPRD1) intronic SNP rs2236861 with non-dependent opioid use (HC vs. NOD) remained significant after correction for multiple testing (OR=0.032; p=0.015). This SNP exhibited a significant gene-gene interaction with prepronociceptin (PNOC) SNP rs2722897 (OR=5.24; p=0.041) (HC vs. NOD).

Conclusions: This study identifies several new and some previously reported associations of variants with heroin dependence and with non-dependent opioid use, an important and difficult to obtain group not extensively studied previously. Further studies are warranted to confirm and elucidate the potential roles of these variants in the vulnerability to illicit drug use and drug addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drugalcdep.2016.08.634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842569PMC
November 2016

HDR: a statistical two-step approach successfully identifies disease genes in autosomal recessive families.

J Hum Genet 2016 Nov 30;61(11):959-963. Epub 2016 Jun 30.

Laboratory of Statistical Genetics, Rockefeller University, New York, NY, USA.

In the search for sequence variants underlying disease, commonly applied filtering steps usually result in a number of candidate variants that cannot further be narrowed down. In autosomal recessive families, disease usually occurs only in one generation so that genetic linkage analysis is unlikely to help. Because homozygous recessive mutations tend to be inherited together with flanking homozygous variants, we developed a statistical method to detect pathogenic variants in autosomal recessive families: We look for differences in patterns of homozygosity around candidate variants between patients and control individuals and expect that such differences are greater for pathogenic variants than random candidate variants. In six autosomal recessive mitochondrial disease families, in which pathogenic homozygous variants have already been identified, our approach succeeded in prioritizing pathogenic mutations. Our method is applicable to single patients from recessive families with at least a few dozen control individuals from the same population; it is easy to use and is highly effective for detecting causative mutations in autosomal recessive families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jhg.2016.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411490PMC
November 2016

African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction.

Pharmacogenomics 2016 06 7;17(9):995-1003. Epub 2016 Jun 7.

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA.

Aim: This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence.

Patients & Methods: The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed.

Results: Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing (Pcorrected = 0.047). CHRM4 is located in a region of strong linkage disequilibrium on chromosome 11 that includes genes associated with schizophrenia. CHRM4 SNP rs2229163 is in strong linkage disequilibrium with several African-specific SNPs in DGKZ and AMBRA1.

Conclusion: Cholinergic receptors' variants may contribute to drug addiction and have a potential role as pharmacogenetic markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2016-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996315PMC
June 2016

Synaptic Plasticity and Signal Transduction Gene Polymorphisms and Vulnerability to Drug Addictions in Populations of European or African Ancestry.

CNS Neurosci Ther 2015 Nov 19;21(11):898-904. Epub 2015 Sep 19.

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.

Aim: Drug addiction is characterized, in part, by deregulation of synaptic plasticity in circuits involved in reward, stress, cue learning, and memory. This study was designed to assess whether 185 variants in 32 genes central to synaptic plasticity and signal transduction contribute to vulnerability to develop heroin and/or cocaine addiction.

Methods: Analyses were conducted in a sample of 1860 subjects divided according to ancestry (African and European) and drug of abuse (heroin or cocaine).

Results: Eighteen SNPs in 11 genes (CDK5R1, EPHA4, EPHA6, FOSL2, MAPK3, MBP, MPDZ, NFKB1, NTRK2, NTSR1, and PRKCE) showed significant associations (P < 0.01), but the signals did not survive correction for multiple testing. SNP rs230530 in the NFKB1 gene, encoding the transcription regulator NF-kappa-B, was the only SNP indicated in both ancestry groups and both addictions. This SNP was previously identified in association with alcohol addiction. SNP rs3915568 in NTSR1, which encodes neurotensin receptor, and SNP rs1389752 in MPDZ, which encodes the multiple PDZ domain protein, were previously associated with heroin addiction or alcohol addiction, respectively.

Conclusions: The study supports the involvement of genetic variation in signal transduction pathways in heroin and cocaine addiction and provides preliminary evidence suggesting several new risk or protective loci that may be relevant for diagnosis and treatment success.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cns.12450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619135PMC
November 2015

Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry.

Prog Neuropsychopharmacol Biol Psychiatry 2016 Jan 12;64:118-23. Epub 2015 Aug 12.

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.

Background: Drug addiction, a leading health problem, is a chronic brain disease with a significant genetic component. Animal models and clinical studies established the involvement of glutamate and GABA neurotransmission in drug addiction. This study was designed to assess if 258 variants in 27 genes of these systems contribute to the vulnerability to develop drug addiction.

Methods: Four independent analyses were conducted in a sample of 1860 subjects divided according to drug of abuse (heroin or cocaine) and ancestry (African and European).

Results: A total of 11 SNPs in eight genes showed nominally significant associations (P<0.01) with heroin and/or cocaine addiction in one or both ancestral groups but the associations did not survive correction for multiple testing. Of these SNPs, the GAD1 upstream SNP rs1978340 is potentially functional as it was shown to affect GABA concentrations in the cingulate cortex. In addition, SNPs GABRB3 rs7165224; DBI rs12613135; GAD1 SNPs rs2058725, rs1978340, rs2241164; and GRIN2A rs1650420 were previously reported in associations with drug addiction or related phenotypes.

Conclusions: The study supports the involvement of genetic variation in the glutamatergic and GABAergic systems in drug addiction with partial overlap in susceptibility loci between cocaine and heroin addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2015.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564302PMC
January 2016

Susceptibility loci for heroin and cocaine addiction in the serotonergic and adrenergic pathways in populations of different ancestry.

Pharmacogenomics 2015 31;16(12):1329-42. Epub 2015 Jul 31.

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA.

Background: Drug addiction is influenced by genetic factors.

Aim: To determine if genetic variants in the serotonergic and adrenergic pathways are associated with heroin and/or cocaine addiction.

Subjects & Methods: The study examined 140 polymorphisms in 19 genes in 1855 subjects with predominantly European or African ancestries.

Results: A total of 38 polymorphisms (13 genes) showed nominal associations, including novel associations in S100A10 (p11) and SLC18A2 (VMAT2). The association of HTR3B SNP rs11606194 with heroin addiction in the European ancestry subgroup remained significant after correction for multiple testing (p(corrected) = 0.04).

Conclusion: The study strengthens our previous findings of association of polymorphisms in HTR3A, HTR3B and ADRA1A. The study suggests partial overlap in genetic susceptibility between populations of different ancestry and between heroin and cocaine addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs.15.86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896084PMC
June 2016

Leveling the Playing Field in Homozygosity Mapping Using Map Distances.

Ann Hum Genet 2015 Sep 15;79(5):366-372. Epub 2015 Jul 15.

McGill University and Genome Québec Innovation Centre, Montreal, Canada.

Studies of linkage disequilibrium (LD) and its variation in the genome are of central importance for understanding evolutionary history, population structure, and selective sweeps. Extreme forms of the latter may result in runs of homozygosity (ROH). In human gene mapping, long ROHs are the basis for homozygosity mapping (HM) with length measured in terms of Mb (10 base pairs physical distance). LD varies greatly over the human genome so that long ROHs tend to occur preferentially in regions of high LD and ROHs of the same length in different regions are not strictly comparable. Thus, in human gene mapping, LD appears as a confounder that needs to be taken into account in the interpretation of ROHs. The effect of varying LD can be mitigated by working on a scale of centimorgans (cM, genetic distance) instead of Mb. We demonstrate this effect for HapMap 3 data on chromosome 19 and show examples with different ROH lengths depending on whether physical or genetic lengths are used. These results suggest that HM should preferably be done on genetic rather than physical distances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12125DOI Listing
September 2015

Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing.

Sci Rep 2015 Jul 6;5:12028. Epub 2015 Jul 6.

Institute of Psychology, Chinese Academy of Sciences, Beijing, China 100101; and Rockefeller University, New York, NY 10065, USA.

A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usually result in a list of candidate variants that cannot be narrowed down further or ranked. To prioritize shortlisted SNVs we consider each homozygous candidate variant together with a set of SNVs flanking it. We compare the resulting array of genotypes between an affected family member and a number of control individuals and argue that, in a family, differences between family member and controls should be larger for a pathogenic variant and SNVs flanking it than for a random variant. We assess differences between arrays in two individuals by the Hamming distance and develop a suitable test statistic, which is expected to be large for a causative variant and flanking SNVs. We prioritize candidate variants based on this statistic and applied our approach to six patients with known pathogenic variants and found these to be in the top 2 to 10 percentiles of ranks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep12028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155624PMC
July 2015

Common Regulatory Variants of CYFIP1 Contribute to Susceptibility for Autism Spectrum Disorder (ASD) and Classical Autism.

Ann Hum Genet 2015 Sep 19;79(5):329-340. Epub 2015 Jun 19.

Institutes of Brain Science, Fudan University, Shanghai, China.

Based on the analysis of mRNA expression and genotype data from the "Brain Cloud" database, we identified seven SNPs within or near the autism candidate gene CYFIP1 that show nominally significant correlations between genotype and CYFIP1 mRNA expression in human dorsolateral prefrontal cortex. Analysis of transmission disequilibrium test (TDT) odds ratios (ORs) for these SNPs in a large Autism Genome Project (AGP) trio-based association study revealed the high-expression alleles of four of these SNPs (rs8028440, rs2289823, rs7403800 and rs3751566) to be susceptibility alleles. Correlations between the regression coefficients for mRNA expression and log -transformed TDT ORs were statistically significant [P = 0.008 (ASD); P = 0.002 (classical autism)]. Similarly, statistically significant correlations were obtained between levels of CYFIP1 mRNA expression predicted using the regression equations obtained from multiple linear regression analysis and log -transformed TDT ORs for specific combinations of genotypes for both ASD (rs2289823 + rs3751566: P = 0.008) and classical autism (rs2289823 + rs3751566: P = 0.008; rs2289823 + rs3751566 + rs765763: P = 0.0006) diagnoses. Together, these results support the hypothesis that high expression of CYFIP1 mRNA increases susceptibility for both ASD and classical autism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12121DOI Listing
September 2015

PDE3A mutations cause autosomal dominant hypertension with brachydactyly.

Nat Genet 2015 Jun 11;47(6):647-53. Epub 2015 May 11.

1] Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [2] Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3302DOI Listing
June 2015

Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans.

Ann Hum Genet 2015 May 27;79(3):188-98. Epub 2015 Feb 27.

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.

Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single-marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7-SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399004PMC
May 2015