Alcohol addiction may increase the risk of obesity due to shared genetic components. The Copine V (CPNE5) gene is involved in Ca2+ binding and may play an important role in the development of the central nervous system. This study tested the genetic associations of 77 single-nucleotide polymorphisms (SNPs) within the CPNE5 gene with alcohol dependence (AD) and obesity using a Caucasian sample - The Study of Addiction - Genetics and Environment (SAGE) sample (1066 AD cases and 1278 non-AD controls, 422 obese cases and 1395 non-obese controls). The Marshfield sample (1442 obese cases and 2122 non-obese controls) was used for replication of obesity. Multiple logistic regression analysis was performed using the PLINK software. In the SAGE sample, we identified 10 SNPs associated with AD and 17 SNPs associated with obesity (p < 0.05). Interestingly, 6 SNPs (rs9986517, rs9470387, rs3213534, rs10456444, rs3752482, and rs9470386) were associated with both AD (OR = 0.77, 0.77, 0.83, 0.84, 0.79 and 1.14, respectively; p = 9.72 × 10-5, 1.1 × 10-4, 4.09 × 10-3, 5.26 × 10-3, 1.59 × 10-2, and 3.81 × 10-2, respectively) and obesity (OR = 0.77, 0.77, 0.78, 0.77, 0.68 and 1.18, respectively; p = 2.74 × 10-3, 2.69 × 10-3, 2.45 × 10-3, 1.01 × 10-3, 5.18 × 10-3 and 3.85 × 10-2, respectively). In the Marshfield sample, rs3752480 was associated with obesity (p = 0.0379). In addition, four SNPs (rs9986517, rs10456444, rs7763347 and rs4714010) showed associations with obesity in the meta-analysis using both samples (p = 0.00493, 0.0274, 0.00346, and 0.0141, respectively). These findings provide the first evidence of common genetic variants in the CPNE5 gene influencing both the AD and obesity; and will serve as a resource for replication in other populations.

The DPYSL2 gene at 8p22-p21 is expressed widely in neuronal tissues and has been implicated in multiple psychiatric disorders such as Alzheimer's disease and schizophrenia. We therefore hypothesized that DPYSL2 gene polymorphisms may play a role in alcohol dependence (AD). We investigated the genetic associations of 57 single-nucleotide polymorphisms (SNPs) within the DPYSL2 gene with AD using two Caucasian samples - the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls), and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). The SNP rs11995227 was most significantly associated with AD (p = 0.000122) in the COGA sample while one flanking SNP rs7832576 revealed the second most significant association with AD (p = 0.00163) in the COGA sample and association with AD (p = 0.0195) in the SAGE sample. Meta-analysis of two samples showed both rs119952227 and rs7832576 were associated with AD (p = 0.000363 and 0.000184, respectively). Furthermore, the C-A haplotype from rs11995227 and rs7832576 revealed significant association with AD (p = 0.0000899) in the COGA sample while the T-G haplotype revealed association with AD both in the COGA and SAGE samples (p = 0.00098 and 0.021, respectively). These findings suggest that genetic variants in DPYSL2 may play a role in susceptibility to AD.

Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p<10 -4. The first best signal was rs770182 (p = 3.65 × 10 -6) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p<10 -4 (p = 7.15 × 10 -6, 2.79 × 10 -5 and 4.93 × 10 -5, respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10 -4 in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10 -4 and 9.48 × 10 -5, respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p<10 -2) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.

Formal thought disorder (FTD), or disorganized speech, is one of the central signs of schizophrenia; however, little is known about the etiology of FTD. To identify new genetic loci associated with FTD, we conducted the first genome-wide association meta-analysis of two datasets of 835 cases of FTD and 2,694 controls with 729,454 single-nucleotide polymorphisms (SNPs). Logistic regression analysis of FTD as a binary trait, adjusted for age and sex, was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 61 SNPs associated with FTD with p < 10-4. The most significant association with FTD was observed with rs1783925 (p = 4.4 × 10-7) within PKNOX2 gene at 11q24.2 while the second interesting locus was rs2277644 (p = 1.18 × 10-5) within MYH13 at 17p13. Haplotype analyses of PKNOX2 and MYH13 loci further supported the associations with FTD. The third locus was PHF2 at 9q22.31 (the top SNP was rs12238738 with p = 2.08 × 10-5) while the fourth locus was GPC6 at 13q32 (the top SNP was rs17196161 with p = 3.12 × 10-5). In conclusion, we identified four new loci (PKNOX2, MYH13, PHF2, and GPC6) associated with FTD. These findings offer the potential for new insights into the pathogenesis of FTD and schizophrenia.

We performed a genome-wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene×gender interactions for AAO in schizophrenia (SCZ) using a European-American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene×gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P=3.10×10-7) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P=4.30×10-6) and the third region was at 4p16.1 (rs17407555, P=4.56×10-6, near RAF1P1, and rs4697924, P=1.23×10-5 within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P=2.10×10-6 and 2.33×10-6, respectively) and strong gene×gender interactions in influencing AAO (P=9.23×10-7 and 1.15×10-6, respectively) while the second best region showing gene×gender interaction was at 7q22.3 (rs179863, P=2.33×10-6). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P<0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ.

The MAPT gene has been shown to be associated with several neurodegenerative disorders, including forms of parkinsonism and Parkinson disease (PD), but the results reveal population differences. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 with PD and age at onset, by using 443 discordant sib pairs in PD from a public dataset (Mayo-Perlegen LEAPS Collaboration). Association with PD was assessed by the FBAT using generalized estimating equations (FBAT-GEE), while the association with age at onset as a quantitative trait was evaluated using the FBAT-logrank statistic. Five SNPs were significantly associated with PD (P < 0.05) in an additive model, and 9 SNPs were associated with PD (P < 0.05) in dominant and recessive models. Interestingly, 8 PD-associated SNPs were also associated with age at onset of PD (P < 0.05) in dominant and recessive models. The SNP most significantly associated with PD and age at onset was rs17649641 (P = 0.015 and 0.021, respectively). Two-SNP haplotypes inferred from rs17563965 and rs17649641 also showed association with PD (P = 0.018) and age at onset (P = 0.026). These results provide further support for the role of MAPT in development of PD.

The evolution of antibiotic resistance provides a well-documented, rapid, and recent example of a selection driven process that has occurred in many bacterial species. An exhaustive collection of Moraxella catarrhalis that spans a transition to chromosomally encoded penicillin resistance was used to analyze genetic changes accompanying the transition. The population was characterized by high haplotypic diversity with 148 distinct haplotypes among 372 isolates tested at three genomic regions. The power of a temporally stratified sample from a single population was highlighted by the finding of high genetic diversity throughout the transition to resistance, population numbers that remained high over time, and no evidence of departures from neutrality in the allele frequency spectra throughout the transition. The direct temporal analysis documented the persistence, antibiotic status, and haplotypic identity of strains undergoing apparent clonal expansions. Several haplotypes that were β-lactamase nonproducers in early samples converted to producers in later years. Maintenance of genetic diversity and haplotype conversions from sensitive to resistant supported the hypothesis that penicillin resistance determinants spread to a diverse array of strains via horizontal exchange. Genetic differentiation between sample years, estimated by FST, was increasing at a rate that could cause complete haplotype turnover in less than 150 years. Widespread linkage disequilibrium among sites within one locus (copB) suggested recent mutation followed by clonal expansion. Nonrandom associations between haplotypes and resistance phenotypes provided further evidence of clonal expansion for some haplotypes. Nevertheless, the population structure was far from clonal as evidenced by a relatively low frequency of disequilibria both within sites at a second locus (M46) as well as between loci. The haplotype-antibiotic resistance association that was accompanied by gradual haplotype turnover is consistent with a hypothesis of genetic drift at marker loci with directional selection at the resistance locus.

Background The pleckstrin and Sec7 domain-containing 3 (PSD3) gene has been linked to immune diseases. We examined whether the genetic variants within the PSD3 gene are associated with obesity, type 2 diabetes (T2D), and high-density lipoprotein (HDL) cholesterol level. Methods Multiple logistic regression model and linear regression model were used to examine the associations of 259 single nucleotide polymorphisms (SNPs) within the PSD3 gene with obesity and T2D as binary traits, and HDL level as a continuous trait using the Marshfield data, respectively. A replication study of obesity was conducted using the Health Aging and Body Composition (Health ABC) sample. Results 23 SNPs were associated with obesity (p < 0.05) in the Marshfield sample and rs4921966 revealed the strongest association (p = 3.97 × 10−6). Of the 23 SNPs, 20 were significantly associated with obesity in the meta-analysis of two samples (p < 0.05). Furthermore, 6 SNPs revealed associations with T2D in the Marshfield data (top SNP rs12156368 with p = 3.05 × 10−3); while two SNPs (rs6983992 and rs7843239) were associated with both obesity and T2D (p = 0.0188 and 0.023 for obesity and p = 8.47 × 10−3 and 0.0128 for T2D, respectively). Furthermore, 11 SNPs revealed associations with HDL level (top SNP rs13254772 with p = 2.79 × 10−3) in the Marshfield data; meanwhile rs7009615 was associated with both T2D (p = 0.038) and HDL level (p = 4.44 × 10−3). In addition, haplotype analyses further supported the results of single SNP analysis. Conclusions Common variants in PSD3 were associated with obesity, T2D and HDL level. These findings add important new insights into the pathogenesis of obesity, T2D and HDL cholesterol.

En sélection génomique, des marqueurs de l’ADN sont utilisés pour l’évaluation des grandes races laitières. La plupart des méthodes d’évaluation génomique actuelles utilisent des SNP, bien que l’utilisation d’haplotypes de SNP apporte un plus grand polymorphisme. Il n’y avait pas d’évaluation génomique en place en 2014 pour les races régionales (Abondance, Tarentaise, Vosgienne), plaçant ces races en position de faiblesse.Notre objectif principal a été de mesurer l’intérêt de l’utilisation d’haplotypes en évaluation génomique, y compris à partir d’une population d’apprentissage multiraciale. Nous avons montré que les haplotypes conduisent à de meilleurs résultats que les SNP et que la fréquence des allèles et l’étendu du déséquilibre de liaison sont importants pour une construction optimale des haplotypes. Nous avons développé deux critères incorporant ces informations qui améliorent la précision des évaluations tout en réduisant le nombre de marqueurs utilisés.Depuis 2015, un de ces critères a été inclus dans les évaluations génomiques officielles en France. Notre approche a donné dans les races régionales une précision similaire à celle obtenue après testage sur descendance. Une évaluation génomique de routine est en place pour 3 races régionales en France depuis Juin 2016. L’utilisation d’une puce Haute Densité n’a pas amélioré sa précision, alors qu’une population d’apprentissage multiraciale a été bénéfique uniquement pour certaines races. Le génotypage des nouvelle femelles a augmenté la précision de la sélection mais l’inclusion de mutations candidates détectées dans les grandes races laitières n’a conduit qu’à une légère amélioration chez les races régionales. / In genomic selection, DNA marker information is exploited for evaluation purposes in large dairy cattle breeds. Most of the current genomic evaluation methods rely today on SNP information, although haplotypes are expected to perform better due to their higher polymorphism. In 2014, genomic evaluation had not yet been implemented in regional breeds (Abondance, Tarentaise, Vosgienne), resulting in economic weaknesses for these breeds.Our aim was to assess the use of haplotypes in genomic evaluation with focus on their performance in combination with multi-breed reference populations. We found that haplotypes outperformed individual SNP markers for genomic evaluation. We also showed that information on haplotype allele frequency and on linkage pattern are relevant to select haplotypes for evaluation purposes. Our haplotype selection criteria also allowed a significant reduction of the number of markers used for genomic prediction.One of these criteria was incorporated into the French routine genomic evaluation in 2015. The performance of such an evaluation was then assessed in four regional breeds, leading to similar or higher accuracies than current progeny testing. Consequently, routine genomic evaluation was implemented in these breeds in 2016. The use of high density genotypes did not improve the performance of genomic evaluation in these breeds, while multi-breed training populations were beneficial only in some of them. Additional genotyped females led to notable increases in selection accuracies. Inclusion of candidate mutations identified in large breeds led to only minor improvements in regional breeds.

Abstract Parkinson’s disease and Huntington’s disease are progressive neurodegenerative movement disorders that typically manifest in adulthood. In this study, genetic risk factors contributing to these two movement disorders were investigated in Finnish patients. Patients with early-onset or late-onset Parkinson’s disease as well as population controls were examined. The p.L444P mutation in GBA was found to contribute to the risk of Parkinson’s disease. POLG1 compound heterozygous mutations were detected in two patients with Parkinson’s disease and rare length variants in POLG1 were associated with Parkinson’s disease. Variants in SMPD1, LRRK2 or CHCHD10, previously detected in other populations, were not detected, suggesting that they are rare or even absent in the Finnish population. Patients with Huntington’s disease were investigated for HTT gene haplotypes as well as whether these haplotypes alter the stability of the elongated CAG repeat. Haplogroup A was less common in Finns than in other European populations, whereas it was significantly more common in patients with Huntington’s disease than in the general population. Certain HTT haplotypes as well as the parental gender were found to affect the repeat instability. We found that compound heterozygous mutations in POLG1 were causative of Parkinson’s disease, rare length variants in POLG1 were associated with Parkinson’s disease and GBA p.L444P was significantly more frequent in patients than in the controls, which suggests that these mutations are associated with the development of Parkinson’s disease. The low prevalence of Huntington’s disease in Finland correlates with the low frequency of the disease-associated HTT haplogroup A. Paternal inheritance combined with haplotype A1 increased the risk of repeat expansion. Movement disorders in Finland were found to share some of the same genetic risk factors found in other European populations, but some other recognized genetic variants could not be detected. / Tiivistelmä Parkinsonin tauti ja Huntingtonin tauti ovat hermostoa rappeuttavia eteneviä liikehäiriösairauksia, jotka tyypillisesti ilmenevät aikuisiällä. Tässä tutkimuksessa selvitettiin näiden kahden liikehäiriösairauden geneettisiä riskitekijöitä suomalaisilla potilailla. Tutkimme potilaita, joilla oli varhain alkava Parkinsonin tauti tai myöhään alkava Parkinsonin tauti sekä väestökontrolleja. GBA-geenin p.L444P mutaation havaittiin lisäävän Parkinsonin taudin riskiä. Kaksi Parkinsonin tautia sairastavaa potilasta oli yhdistelmäheterotsygootteja haitallisten POLG1-geenin varianttien suhteen ja harvinaiset POLG1 CAG toistojaksovariantit assosioituivat Parkinsonin tautiin. Tutkittuja variantteja SMPD1-, LRRK2- ja CHCHD10-geeneissä ei löydetty tästä aineistosta lainkaan, mikä viittaa siihen, että ne puuttuvat suomalaisesta väestöstä tai ovat harvinaisia. Huntingtonin tautia sairastavilta potilailta tutkittiin HTT-geenin haploryhmiä ja niiden vaikutusta Huntingtonin tautia aiheuttavan pidentyneen toistojakson epästabiiliuteen. Haploryhmä A oli suomalaisessa väestössä harvinainen verrattuna eurooppalaiseen väestöön ja se oli huomattavasti yleisempi Huntingtonin tautipotilailla kuin väestössä. Toistojakson epästabiiliuteen vaikuttivat tietyt HTT-geenin haplotyypit samoin kuin sen vanhemman sukupuoli, jolta pidentynyt toistojakso periytyy. POLG1 yhdistelmäheterotsygoottien katsottiin aiheuttavat Parkinsonin tautia ja harvinaisten POLG1 CAG toistojaksovarianttien todettiin assosioituvan Parkinsonin tautiin Suomessa. GBA p.L444P mutaatio merkittävästi yleisempi Parkinsonin tautipotilailla kuin kontrolleilla, mikä viittaa siihen, että se on Parkinsonin taudin riskitekijä. Huntingtonin tautiin assosioituvan haploryhmä A:n matala frekvenssi selittää taudin vähäistä esiintyvyyttä Suomessa. Paternaalinen periytyminen ja haplotyyppi A1 lisäsivät HTT-geenin toistojakson pidentymisen riskiä. Liikehäiriösairauksilla todettiin Suomessa osittain samanlaisia riskitekijöitä kuin muualla Euroopassa, mutta kaikkia tutkittuja variantteja emme havainneet.