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      Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

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          Abstract

          Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified( 1). We performed an exome-chip based GWAS in 2,158 cases from nine populations of European origin and 15,485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common, 5 rare). No findings reached genome-wide significance. Two notable common variants were identified; rs10791286, an intronic variant in OPCML (p=9.89x10 -6), and rs7700147, an intergenic variant (p=2.93x10 -5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

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          Most cited references96

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          Genome-wide association studies for complex traits: consensus, uncertainty and challenges.

          The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
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            Risk alleles for multiple sclerosis identified by a genomewide study.

            Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. Copyright 2007 Massachusetts Medical Society.
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              Epidemiology of eating disorders in Europe: prevalence, incidence, comorbidity, course, consequences, and risk factors.

              Eating disorders - anorexia nervosa, bulimia nervosa, and binge eating disorder - affect numerous Europeans. This narrative review summarizes European studies on their prevalence, incidence, comorbidity, course, consequences, and risk factors published in 2015 and the first half of 2016.
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                Author and article information

                Journal
                9607835
                20545
                Mol Psychiatry
                Mol. Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                18 March 2017
                25 July 2017
                07 March 2018
                : 10.1038/mp.2017.88
                Author notes
                Corresponding authors; LM Huckins, E Zeggini, CM Bulik
                [*]

                Joint first authors

                [#]

                Joint last authors

                Article
                EMS71586
                10.1038/mp.2017.88
                5828108
                29155802
                b1cd8416-06d5-4e69-be99-3c59a40d5832

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                Molecular medicine
                Molecular medicine

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