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AbstractThe heritability of the degree of residential area urbanization in twins and their siblings in the Dutch population was examined. The postal code was known for 6879 twins and 2724 siblings registered with the Netherlands Twin Register and born between 1940 and 1983. Using data from Statistics Netherlands (Centraal Bureau voor de Statistiek, 2001), these postal codes could be related to residential area characteristics, including urbanization level. The degree of urbanization was assessed on a 5-point scale: very heavy, heavy, moderate, low and not urbanized. Genetic model-fitting was carried out in three age cohorts: young adults (born 1975 to 1983), adults (born 1965 to 1974) and older adults (born 1940 to1964). Twin and sibling resemblance in urbanization level was expressed in polychoric correlations. These correlations decreased from the youngest cohort (.66 to .86) to the oldest cohort (.20 to .58). In all 3 age cohorts, genetic factors did not contribute to familial resemblance. The influence of common environment decreased in importance from the young cohort (70% to 83%) to the old cohort (46% to 47%) and was lower in women than in men in all but the oldest age cohort. This study did not replicate Australian findings of a genetic contribution in the older cohorts; common environmental factors and, increasingly with age, unique environmental factors determine where the Dutch live. Future studies in European and other populations will reveal whether these results are specific to the Dutch population.

Although it is well established that experience seeking behavior (ES) is
positively related to cognitive functioning, the mechanisms underlying this
association are not clearly understood. In a large sample of adult twins and
siblings (N = 864, age range 23–75), we studied the causes of
covariation between ES and general cognitive ability and we studied whether ES
moderates the genetic and environmental causes of variation in general cognitive
ability. Results demonstrate a phenotypic correlation of .17 (p <.001)
between general cognitive ability and ES, with a common genetic and common
environmental background. Moreover, the extent to which genetic and
environmental factors are shared between general cognitive ability and ES is
increased in individuals with either lower or higher levels of ES. In addition,
the extent to which genetic and environmental factors influence individual
differences in general cognitive ability in adults partly depended on ES.
Standardized influences of additive genetic factors on general cognitive ability
ranged from 13% to 99%, with lower estimates in higher levels of ES, while
standardized estimates of environmental factors ranged from almost 1% to 87%,
with higher estimates in higher levels of ES. Hence, ES and cognitive ability
are not only associated through common genetic and environmental factors, but
also via moderating effects of genetic and environmental influences on cognitive
ability by ES. These findings have implications for future studies on the
association between ES and general cognitive ability, and for future research on
the genetics of cognitive ability.

AbstractPrevious studies in young and adolescent twins suggested substantial genetic contributions to the amplitude and latency of the P3 evoked by targets in an oddball paradigm. Here we examined whether these findings can be generalized to adult samples. A total of 651 twins and siblings from 292 families participated in a visual oddball task. In half of the subjects the age centered around 26 (young adult cohort), in the other half the age centered around 49 (middle-aged adult cohort). P3 peak amplitude and latency were scored for 3 midline leads Pz, Cz, and Fz. No cohort differences in heritability were found. P3 amplitude (∼50%) and latency (∼45%) were moderately heritable for the 3 leads. A single genetic factor influenced latency at all electrodes, suggesting a single P3 timing mechanism. Specific genetic factors influenced amplitude at each lead, suggesting local modulation of the P3 once triggered. Genetic analysis of the full event-related potential waveform showed that P3 heritability barely changes from about 100 ms before to 100 ms after the peak. Age differences are restricted to differences in means and variances, but the proportion of genetic variance as part of the total variance of midline P3 amplitude and latency does not change from young to middle-aged adulthood.

AbstractThe hypothesis was tested that monozygotic (MZ) and dizygotic (DZ) twins, with their lower average birth weight, have higher adult blood pressure than their singleton brothers or sisters. From the Netherlands Twin Registry, 261 twin families were recruited from a young adult and an older adult cohort with mean ages of 26.2 and 50.4 respectively. These families yielded 204 MZ twins with 71 singleton siblings and 271 DZ twins with 103 of their singleton siblings. Anti-hypertensive medication use of these 649 participants was assessed twice with a two-year interval. Resting blood pressure was measured thrice during a standardized laboratory protocol. In spite of a significant difference in birth weight (1036 gram), no differences were found in anti-hypertensive medication use at both time points between twins and singletons nor between their resting laboratory diastolic or systolic blood pressure. These results applied to each gender and to both age cohorts. Limiting the analyses to matched twin-sibling pairs of the same families and taking current weight and height into account did not change the results; no evidence was found for a twin-singleton difference. It was concluded that estimates of genetic and environmental contributions to blood pressure deriving from twin studies do not appear to be biased and may be generalized to singletons. Our results suggest that the lower birth weight in twins does not reflect the intrauterine disadvantage described by the Barker hypothesis.

AbstractThrough its ability to induce the enhanced release and production of cytokines, amyloid-β is responsible for the chronic inflammatory response that contributes to Alzheimer's disease (AD). Determining whether the response of monocytes to amyloid-β stimulation is under genetic control may help understand the basis of why some people are more prone to develop neuronal degeneration than others. In the current study we investigated the heritability of the cytokine (IL-10, IL-6, IL-1β, IL-1ra, TNF-[.alpha]) production capacity upon ex vivo stimulation with amyloid-β in whole blood samples of 222 twins and 85 singleton siblings from 139 extended twin families. It was found that individual differences in amyloid-β-induced cytokine production capacity are to a large extent of genetic origin, with heritability estimates ranging from 55% (IL-1β) to 68% (IL-6). We conclude that genes influencing amyloid-β-induced cytokine response may provide clues to the progression of AD pathology.

AbstractIn the late 1980s The Netherlands Twin Register (NTR) was established by recruiting young twins and multiples at birth and by approaching adolescent and young adult twins through city councils. The Adult NTR (ANTR) includes twins, their parents, siblings, spouses and their adult offspring. The number of participants in the ANTR who take part in survey and / or laboratory studies is over 22,000 subjects. A special group of participants consists of sisters who are mothers of twins. In the Young NTR (YNTR), data on more than 50,000 young twins have been collected. Currently we are extending the YNTR by including siblings of twins. Participants in YNTR and ANTR have been phenotyped every 2 to 3 years in longitudinal survey studies, since 1986 and 1991 for the YNTR and ANTR, respectively. The resulting large population-based datasets are used for genetic epidemiological studies and also, for example, to advance phenotyping through the development of new syndrome scales based on existing items from other inventories. New research developments further include brain imaging studies in selected and unselected groups, clinical assessment of psychopathology through interviews, and cross-referencing the NTR database to other national databases. A large biobank enterprise is ongoing in the ANTR in which blood and urine samples are collected for genotyping, expression analysis, and meta-bolomics studies. In this paper we give an update on the YNTR and ANTR phenotyping and on the ongoing ANTR biobank studies.

AbstractAmultidisciplinary collaborative study examining cognition in a large sample of twins is outlined. A common experimental protocol and design is used in The Netherlands, Australia and Japan to measure cognitive ability using traditional IQ measures (i.e., psychometric IQ), processing speed (e.g., reaction time [RT] and inspection time [IT]), and working memory (e.g., spatial span, delayed response [DR] performance). The main aim is to investigate the genetic covariation among these cognitive phenotypes in order to use the correlated biological markers in future linkage and association analyses to detect quantitativetrait loci (QTLs). We outline the study and methodology, and report results from our preliminary analyses that examines the heritability of processing speed and working memory indices, and their phenotypic correlation with IQ. Heritability of Full Scale IQ was 87% in the Netherlands, 83% in Australia, and 71% in Japan. Heritability estimates for processing speed and working memory indices ranged from 33–64%. Associations of IQ with RT and IT (−0.28 to −0.36) replicated previous findings with those of higher cognitive ability showing faster speed of processing. Similarly, significant correlations were indicated between IQ and the spatial span working memory task (storage [0.31], executive processing [0.37]) and the DR working memory task (0.25), with those of higher cognitive ability showing better memory performance. These analyses establish the heritability of the processing speed and working memory measures to be used in our collaborative twin study of cognition, and support the findings that individual differences in processing speed and working memory may underlie individual differences in psychometric IQ.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. in addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. in addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. the results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures. ; Judah Foundation ; NIH ; Tourette Syndrome Association International Consortium for Genetics (TSAICG) ; New Jersey Center for Tourette Syndrome and Associated Disorders ; NIMH ; Obsessive Compulsive Foundation ; Ontario Mental Health Foundation ; Tourette Syndrome Association ; American Academy of Child and Adolescent Psychiatry (AACAP) ; Anxiety Disorders Association of America (ADAA) ; University of British Columbia ; Michael Smith Foundation ; American Recovery and Re-investment Act (ARRA) ; Australian Research Council ; Australian National Health and Medical Research Council ; German Research Foundation ; NIH Genes, Environment and Health Initiative [GEI] ; Gene Environment Association Studies (GENEVA) under GEI ; NIH GEI ; National Institute on Alcohol Abuse and Alcoholism ; National Institute on Drug Abuse ; Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA ; Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat,Sch Med, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA USA ; Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA ; Univ Chicago, Dept Med, Chicago, IL 60637 USA ; Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA ; Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands ; Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA ; Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia ; Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia ; Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada ; Hosp Sick Children, Toronto, ON M5G 1X8, Canada ; Univ Vita Salute San Raffaele, Milan, Italy ; Hadassah Hebrew Univ Med Ctr, Herman Dana Div Child & Adolescent Psychiat, Jerusalem, Israel ; Univ Pontificia Bolivariana, Univ Antioquia, Medellin, Colombia ; Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA ; Yale Univ, Dept Psychiat, New Haven, CT 06520 USA ; Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA ; North Shore Long Isl Jewish Med Ctr, Manhasset, NY USA ; NYU Med Ctr, New York, NY 10016 USA ; North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA ; Hofstra Univ, Sch Med, Hempstead, NY 11550 USA ; Inst Nacl Psiquiatria Ramon de la Fuente Muniz, Mexico City, DF, Mexico ; UCL, London, England ; Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China ; Univ São Paulo, Sch Med, Dept Psychiat, São Paulo, Brazil ; Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands ; Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands ; Altrecht Acad Anxiety Ctr, Utrecht, Netherlands ; Univ Milan, Osped San Raffaele, I-20127 Milan, Italy ; Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA ; Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA ; Univ Montreal, Montreal, PQ, Canada ; Univ Calif Los Angeles, Keck Sch Med, Div Biostat, Dept Preventat Med, Los Angeles, CA USA ; Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA ; Univ Ghent, Lab Pharmaceut Biotechnol, B-9000 Ghent, Belgium ; Inst Pasteur, Paris, France ; French Natl Sci Fdn, Fondat Fondamental, Creteil, France ; Hop Robert Debre, AP HP, Dept Child & Adolescent Psychiat, F-75019 Paris, France ; Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada ; Univ Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-97070 Wurzburg, Germany ; Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany ; Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA ; Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp,OCD Program, Boston, MA 02115 USA ; Univ Med Greifswald, Helios Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany ; Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA ; Shaare Zedek Med Ctr, Neuropediatr Unit, Jerusalem, Israel ; Rutgers State Univ, Dept Genet, Human Genet Inst New Jersey, Piscataway, NJ USA ; Univ Stellenbosch, Dept Psychiat, ZA-7600 Stellenbosch, South Africa ; Univ São Paulo, Fac Med, Dept Psychiat, BR-05508 São Paulo, Brazil ; Baylor Coll Med, Dept Neurol, Parkinsons Dis Ctr, Houston, TX 77030 USA ; Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA ; Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA ; Ctr Addict & Mental Hlth, Neurogenet Sect, Toronto, ON, Canada ; Univ Toronto, Dept Psychiat, Toronto, ON, Canada ; Yale Univ, Sch Med, Dept Genet, Yale Child Study Ctr, New Haven, CT 06510 USA ; Overlook Hosp, Atlantic Neurosci Inst, Summit, NJ USA ; Carracci Med Grp, Mexico City, DF, Mexico ; Inst Mondor Rech Biomed, Creteil, France ; Yale Univ, Ctr Child Study, New Haven, CT 06520 USA ; Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany ; Univ Illinois, Dept Psychiat, Inst Human Genet, Chicago, IL 60612 USA ; Univ Stellenbosch, Dept Psychiat, MRC Unit Anxiety & Stress Disorders, ZA-7600 Stellenbosch, South Africa ; Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA ; UCI, Sch Med, Dept Psychiat & Human Behav, Irvine, CA USA ; Univ Utah, Salt Lake City, UT USA ; NIMH Intramural Res Program, Clin Sci Lab, Bethesda, MD USA ; Med City Dallas Hosp, Dept Clin Res, Dallas, TX USA ; Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands ; Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA ; Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA ; Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA ; Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA ; Yale Univ, Dept Psychol, New Haven, CT 06520 USA ; Partners Psychiat & McLean Hosp, Boston, MA USA ; Sunnybrook Hlth Sci Ctr, Frederick W Thompson Anxiety Disorders Ctr, Toronto, ON M4N 3M5, Canada ; St George Hosp, London, England ; Sch Med, London, England ; Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica ; Universidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, Brazil ; Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USA ; Detroit Med Ctr, Detroit, MI USA ; McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada ; Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany ; Univ Fed Bahia, Univ Hlth Care Serv SMURB, Salvador, BA, Brazil ; Youthdale Treatment Ctr, Toronto, ON, Canada ; Johns Hopkins Univ Sch Med, Baltimore, MD USA ; Univ Cape Town, ZA-7925 Cape Town, South Africa ; Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands ; Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Psychiat, Nashville, TN 37235 USA ; Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pediat & Pharmacol, Nashville, TN 37235 USA ; Vanderbilt Univ, Inst Brain, Nashville, TN 37235 USA ; Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland ; Univ Wurzburg, Dept Child & Adolescent Psychiat, D-97070 Wurzburg, Germany ; Univ Amsterdam, Acad Med Ctr, Ctr Psychiat, NL-1105 BC Amsterdam, Netherlands ; Inst Royal Netherlands Acad Arts & Sci NIN KNAW, Netherlands Inst Neurosci, Amsterdam, Netherlands ; NIMH Intramural Res Program, Unit Stat Genom, Bethesda, MD USA ; Univ Utah, Dept Psychiat, Salt Lake City, UT USA ; Natl Inst Genom Med SAP, Carracci Med Grp, Mexico City, DF, Mexico ; Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands ; Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands ; Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands ; Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA ; Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands ; German Ctr Neurodegenerat Dis, Tubingen, Germany ; Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada ; Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands ; Univ British Columbia, British Columbia Mental Hlth & Addict Res Inst, Vancouver, BC V5Z 1M9, Canada ; Brigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USA ; Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA ; Universidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, Brazil ; NIH: NS40024 ; NIH: NS16648 ; NIH: MH079489 ; NIH: MH073250 ; NIH: NS037484 ; NIH: 1R01MH079487-01A1 ; NIH: K20 MH01065 ; NIH: R01 MH58376 ; NIH: MH085057 ; NIH: MH079494 ; NIH: HHSN268200782096C ; NIMH: R01MH092293 ; American Recovery and Re-investment Act (ARRA): NS40024-07S1 ; American Recovery and Re-investment Act (ARRA): NS16648-29S1 ; Australian Research Council: FT0991360 ; Australian Research Council: DE130100614 ; Australian National Health and Medical Research Council: 1047956 ; Australian National Health and Medical Research Council: 1052684 ; German Research Foundation: DFG GR 1912/1-1 ; NIH Genes, Environment and Health Initiative [GEI]: U01 HG004422 ; NIH GEI: U01HG004438 ; : R01 MH090937 ; : P50MH094267 ; Web of Science

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation. ; The authors would like to thank the many colleagues who contributed to collection and phenotypic characterisation of the clinical samples, as well as genotyping and analysis of the GWA data. Special mentions are as follows: CGSB participating cohorts: Some of the data utilised in this study were provided by the Understanding Society: The UK Household Longitudinal Study, which is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The data were collected by NatCen and the genome wide scan data were analysed by the Wellcome Trust Sanger Institute. The Understanding Society DAC have an application system for genetics data and all use of the data should be approved by them. The application form is at: https://www.understandingsociety.ac.uk/about/health/data. The Airwave Health Monitoring Study is funded by the UK Home Office, (Grant number 780-TETRA) with additional support from the National Institute for Health Research Imperial College Health Care NHS Trust and Imperial College Biomedical Research Centre. We thank all participants in the Airwave Health Monitoring Study. This work used computing resources provided by the MRC- funded UK MEDical Bioinformatics partnership programme (UK MED-BIO) (MR/L01632X/1). Paul Elliott wishes to acknowledge the Medical Research Council and Public Health England (MR/L01341X/1) for the MRC-PHE Centre for Environment and Health; and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). Paul Elliott is supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Paul Elliott is associate director of the Health Data Research UK London funded by a consortium led by the UK Medical Research Council. SHIP (Study of Health in Pomerania) and SHIP-TREND both represent population-based studies. SHIP is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); grant GR 1912/5-1). SHIP and SHIP-TREND are part of the Community Medicine Research net (CMR) of the Ernst-Moritz-Arndt University Greifswald (EMAU) which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. SNP typing of SHIP and SHIP-TREND using the Illumina Infinium HumanExome BeadChip (version v1.0) was supported by the BMBF (grant 03Z1CN22). LifeLines authors thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke, Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, René Oostergo, Rosalie Visser, Judith Vonk for their work related to data-collection and validation. The authors are grateful to the study participants, the staff from the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. LifeLines Scientific Protocol Preparation: Rudolf de Boer, Hans Hillege, Melanie van der Klauw, Gerjan Navis, Hans Ormel, Dirkje Postma, Judith Rosmalen, Joris Slaets, Ronald Stolk, Bruce Wolffenbuttel; LifeLines GWAS Working Group: Behrooz Alizadeh, Marike Boezen, Marcel Bruinenberg, Noortje Festen, Lude Franke, Pim van der Harst, Gerjan Navis, Dirkje Postma, Harold Snieder, Cisca Wijmenga, Bruce Wolffenbuttel. The authors wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centres delivering data to LifeLines, and all the study participants. Niek Verweij was supported by NWO VENI (016.186.125). Fenland authors thank Fenland Study volunteers for their time and help, Fenland Study general Practitioners and practice staff for assistance with recruitment, and Fenland Study Investigators, Co-ordination team and the Epidemiology Field, Data and Laboratory teams for study design, sample/data collection and genotyping. We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome Chip array. The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Centre staff for their assistance with this project. Patricia B. Munroe, Mark J. Caulfield, and Helen R. Warren wish to acknowledge the NIHR Cardiovascular Biomedical Research Unit at Barts and The London, Queen Mary University of London, UK for support. Mark J. Caulfield are Senior National Institute for Health Research Investigators. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Daniel Barrowdale, Debra Frost, Jo Perkins. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Marc Tischkowitz, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire & Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Claire Foo. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Alex Henderson, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Nazneen Rahman, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Jenny Pope, Sibel Saya, Natalie Taylor, Zoe Kemp and Angela George. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. Understanding Society Scientific Group is funded by the Economic and Social Research Council (ES/H029745/1) and the Wellcome Trust (WT098051). Paul D.P. Pharoah is funded by Cancer Research UK (C490/A16561). SHIP is funded by the German Federal Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); see acknowledgements for details. F.W. Asselbergs is funded by the Netherlands Heart Foundation (2014T001) and supported by UCL Hospitals NIHR Biomedical Research Centre. The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Niek Verweij is supported by Horizon 2020, Marie Sklodowska-Curie (661395) and ICIN-NHI. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, and the Royal Society of Edinburgh. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Paul W. Franks is supported by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, Swedish Heart Lung Foundation (2020389), and Skåne Regional Health Authority. Nicholas J Wareham, Claudia Langenberg, Robert A Sacott, and Jian'an Luan are supported by the MRC (MC_U106179471 and MC_UU_12015/1). The BRIGHT study was supported by the Medical Research Council of Great Britain (Grant Number G9521010D); and by the British Heart Foundation (Grant Number PG/02/128). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. The Exome Chip genotyping was funded by Wellcome Trust Strategic Awards (083948 and 085475). We would also like to thank the Barts Genome Centre staff for their assistance with this project. The ASCOT study and the collection of the ASCOT DNA repository was supported by Pfizer, New York, NY, USA, Servier Research Group, Paris, France; and by Leo Laboratories, Copenhagen, Denmark. Genotyping of the Exome Chip in ASCOT-SC and ASCOT-UK was funded by the National Institutes of Health Research (NIHR). Anna F. Dominiczak was supported by the British Heart Foundation (Grant Numbers RG/07/005/23633, SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). Nilesh J. Samani is supported by the British Heart Foundation and is a Senior National Institute for Health Research Investigator. Panos Deloukas is supported by the British Heart Foundation (RG/14/5/30893), and NIHR, where his work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Centre which is funded by the National Institute for Health Research (NIHR). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M. Frayling. Hanieh Yaghootkar is funded by Diabetes UK RD Lawrence fellowship (grant:17/0005594) Anna Dominiczak was funded by a BHF Centre of Research Excellence Award (RE/13/5/30177) GSCAN participating cohorts: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators: B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut. The study includes eleven different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield, A. Brooks); Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA (L. Almasy), Virginia Commonwealth University (D. Dick), Icahn School of Medicine at Mount Sinai (A. Goate), and Howard University (R. Taylor). Other COGA collaborators include: L. Bauer (University of Connecticut); J. McClintick, L. Wetherill, X. Xuei, Y. Liu, D. Lai, S. O'Connor, M. Plawecki, S. Lourens (Indiana University); G. Chan (University of Iowa; University of Connecticut); J. Meyers, D. Chorlian, C. Kamarajan, A. Pandey, J. Zhang (SUNY Downstate); J.-C. Wang, M. Kapoor, S. Bertelsen (Icahn School of Medicine at Mount Sinai); A. Anokhin, V. McCutcheon, S. Saccone (Washington University); J. Salvatore, F. Aliev, B. Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grande Valley). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. COGA investigators continue to be inspired by their memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. COGA investigators are very grateful to Dr. Bruno Buecher without whom this project would not have existed. The authors also thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK, a GECCO sub-study, also thanks all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. As part of the GECCO sub-studies, CPS-II authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Another GECCO sub-study, HPFS and NHS investigators would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS and HPFS. HPFS and NHS investigators also thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. PLCO, a substudy within GECCO, was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and additionally supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS1, CGEMS pancreatic cancer scan (PanScan)2, 3, and the Lung Cancer and Smoking study4. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., and Drs. Bill Kopp and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. We also thank all participants and staff of the André and France Desmarais Montreal Heart Institute's (MHI) Biobank. The genotyping of the MHI Biobank was done at the MHI Pharmacogenomic Centre and funded by the MHI Foundation. HRS is supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029). Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the University of Michigan School of Public Health. CHDExome+ participating cohorts: BRAVE: The BRAVE study genetic epidemiology working group is a collaboration between the Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK, the Centre for Control of Chronic Diseases, icddr,b, Dhaka, Bangladesh and the National Institute of Cardiovascular Diseases, Dhaka, Bangladesh. CCHS, CIHDS, and CGPS collaborators thank participants and staff of the Copenhagen City Heart Study, Copenhagen Ischemic Heart Disease Study, and the Copenhagen General Population Study for their important contributions. EPIC-CVD: CHD case ascertainment and validation, genotyping, and clinical chemistry assays in EPIC-CVD were principally supported by grants awarded to the University of Cambridge from the EU Framework Programme 7 (HEALTH-F2-2012-279233), the UK Medical Research Council (G0800270) and British Heart Foundation (SP/09/002), and the European Research Council (268834). We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidemiology Unit for sample management and Cambridge Genomic Services for genotyping, Sarah Spackman for data management, and the team at the EPIC-CVD Coordinating Centre for study coordination and administration. MORGAM: The work by MORGAM collaborators has been sustained by the MORGAM Project's recent funding: European Union FP 7 projects ENGAGE (HEALTH-F4-2007-201413), CHANCES (HEALTH-F3-2010-242244) and BiomarCaRE (278913). This has supported central coordination, workshops and part of the activities of the The MORGAM Data Centre, at THL in Helsinki, Finland. MORGAM Participating Centres are funded by regional and national governments, research councils, charities, and other local sources. PROSPER: collaborators have received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2009-223004 PROMIS: The PROMIS collaborators are are thankful to all the study participants in Pakistan. Recruitment in PROMIS was funded through grants available to investigators at the Center for Non-Communicable Diseases, Pakistan (Danish Saleheen and Philippe Frossard) and investigators at the University of Cambridge, UK (Danish Saleheen and John Danesh). Field-work, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, EU Framework 6-funded Bloodomics Integrated Project, Pfizer. We would like to acknowledge the contributions made by the following individuals who were involved in the field work and other administrative aspects of the study: Mohammad Zeeshan Ozair, Usman Ahmed, Abdul Hakeem, Hamza Khalid, Kamran Shahid, Fahad Shuja, Ali Kazmi, Mustafa Qadir Hameed, Naeem Khan, Sadiq Khan, Ayaz Ali, Madad Ali, Saeed Ahmed, Muhammad Waqar Khan, Muhammad Razaq Khan, Abdul Ghafoor, Mir Alam, Riazuddin, Muhammad Irshad Javed, Abdul Ghaffar, Tanveer Baig Mirza, Muhammad Shahid, Jabir Furqan, Muhammad Iqbal Abbasi, Tanveer Abbas, Rana Zulfiqar, Muhammad Wajid, Irfan Ali, Muhammad Ikhlaq, Danish Sheikh and Muhammad Imran. INTERVAL: Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre (www.cambridge-brc.org.uk). The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), and NIHR Research Cambridge Biomedical Research Centre. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference.

25 páginas, 6 figuras, 2 tablas ; Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. ; This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government's LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not ; Peer reviewed