Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ～ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.     

Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome

In 2010, a new recessive cohesinopathy disorder, designated Warsaw breakage syndrome (WABS), was described. The individual with WABS displayed microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Cytogenetic analysis revealed mitomycin C (MMC)-induced chromosomal breakage; however, an additional sister chromatid cohesion defect was also observed. WABS is genetically linked to bi-allelic mutations in the ChlR1/DDX11 gene which encodes a protein of the conserved family of Iron–Sulfur (Fe–S) cluster DNA helicases. Mutations in the budding yeast ortholog of ChlR1, known as Chl1, were known to cause sister chromatid cohesion defects, indicating a conserved function of the gene. In 2012, three affected siblings were identified with similar symptoms to the original WABS case, and found to have a homozygous mutation in the conserved Fe–S domain of ChlR1, confirming the genetic linkage. Significantly, the clinically relevant mutations perturbed ChlR1 DNA unwinding activity. In addition to its genetic importance in human disease, ChlR1 is implicated in papillomavirus genome maintenance and cancer. Although its precise functions in genome homeostasis are still not well understood, ongoing molecular studies of ChlR1 suggest the helicase plays a critically important role in cellular replication and/or DNA repair.     

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.     

Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

We mapped regulatory loci for nearly all protein-coding genes in mammals using comparative genomic hybridization and expression array measurements from a panel of mouse-hamster radiation hybrid cell lines. The large number of breaks in the mouse chromosomes and the dense genotyping of the panel allowed extremely sharp mapping of loci. As the regulatory loci result from extra gene dosage, we call them copy number expression quantitative trait loci, or ceQTLs. The -2log10P support interval for the ceQTLs was <150 kb, containing an average of <2-3 genes. We identified 29,769 trans ceQTLs with -log10P > 4, including 13 hotspots each regulating >100 genes in trans. Further, this work identifies 2,761 trans ceQTLs harboring no known genes, and provides evidence for a mode of gene expression autoregulation specific to the X chromosome.     

Integrated detection and population-genetic analysis of SNPs and copy number variation

Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.8 million genomic locations. By characterizing 270 HapMap samples, we developed a map of human CNV (at 2-kb breakpoint resolution) informed by integer genotypes for 1,320 copy number polymorphisms (CNPs) that segregate at an allele frequency >1%. More than 80% of the sequence in previously reported CNV regions fell outside our estimated CNV boundaries, indicating that large (>100 kb) CNVs affect much less of the genome than initially reported. Approximately 80% of observed copy number differences between pairs of individuals were due to common CNPs with an allele frequency >5%, and more than 99% derived from inheritance rather than new mutation. Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes.     

Glutamate transporter EAAT2: regulation,function, and potential as a therapeutic target for neurological and psychiatric disease

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson’s disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.     

Retrospective evaluation of the effects of human disturbance and goldfish introduction on endangered Pahrump poolfish

Life history data for Pahrump poolfish ( Empetrichthys latos latos ) collected from 1937 to 1975 were organized and analyzed to improve our understanding of changes caused by human habitat disruption and introduced goldfish ( Carassius auratus ) at Manse Spring, Nevada. Pahrump poolfish twice demonstrated their ability to recover numerically from a population crash. The first crash followed a November 1961 introduction of a few goldfish and subsequent removal of vegetation by local ranch children intent on turning Manse Spring into a swimming hole. The second crash followed another major habitat disturbance resulting from an unsuccessful attempt to eradicate goldfish in July 1967. Each crash (1962&ndash;1963 and 1967&ndash;1968) reduced the poolfish population to fewer than 50 adults and was followed by a population recovery to more than 1000. Following the first habitat disruption, changes in poolfish population structure and poolfish diet were observed. These changes caused an increased mortality rate, resulting in disappearance or decline in relative abundance of larger poolfish size classes with a commensurate reduction in production of mature eggs by the population. We detected no additional changes in life history characteristics that could be associated with the second population crash and recovery. We concluded that removal of vegetation in the summer of 1962 and the more extreme habitat disruption and fish handling in June&ndash;July 1967 were human-induced pulse disturbances resulting in poolfish population crashes. We also concluded that the changes in poolfish life history characteristics resulted principally from press disturbances attributable to goldfish. Los datos sobre la historia de vida del pez de poza Pahrump ( Empetrichthys latos latos ), recopilados entre 1937 y 1975, fueron organizados y analizados para ayudar a entender los cambios cusados por la perturbaci&oacute;n antropog&eacute;nica del h&aacute;bitat y por la introducci&oacute;n del carp&iacute;n dorado ( Carassius auratus ) a Manse Spring, Nevada. En dos ocasiones, los peces de poza Pahrump demostraron la habilidad de reponerse num&eacute;ricamente despu&eacute;s de descensos abruptos de la poblaci&oacute;n. El primero fue en noviembre de 1961, despu&eacute;s de la introducci&oacute;n de algunos carpines dorados y subsecuente remoci&oacute;n de vegetaci&oacute;n por ni&ntilde;os de ranchos locales con la intenci&oacute;n de convertir Manse Spring en una poza para nadar. El segundo descenso ocurri&oacute; luego de otra perturbaci&oacute;n de h&aacute;bitat resultado de un intento fallido por erradicar el carp&iacute;n dorado en julio de 1967. Cada descenso (1962&ndash;1963 y 1967&ndash;1968) redujo la poblaci&oacute;n de peces de poza a menos de 50 adultos; y fue seguido por una recuperaci&oacute;n de la poblaci&oacute;n a m&aacute;s de 1000. Despu&eacute;s de la primera perturbaci&oacute;n del h&aacute;bitat y descenso en la poblaci&oacute;n de peces de poza, se observaron cambios en la dieta y la estructura de la poblaci&oacute;n. Aparentemente, estos cambios ocasionaron un ascenso en la tasa de mortalidad, causando la desaparici&oacute;n o disminuci&oacute;n de la abundancia relativa de peces de poza de clases de mayor tama&ntilde;o, con una reducci&oacute;n proporcional en la producci&oacute;n de huevos maduros. No detectamos cambios adicionales en las caracter&iacute;sticas de historia de vida que pudieran estar asociados con el segundo descenso y recuperaci&oacute;n de la poblaci&oacute;n. Concluimos que la remoci&oacute;n de vegetaci&oacute;n en el verano de 1962, y la a&uacute;n mayor perturbaci&oacute;n del h&aacute;bitat y manejo de peces en junio/julio de 1967, fueron perturbaciones inducidas por el humano a modo de &ldquo;pulso&rdquo; que provocaron descensos de la poblaci&oacute;n de peces de poza, y que los cambios en las caracter&iacute;sticas de historia de vida de los peces de poza resultaron principalmente de la presi&oacute;n por la alteraci&oacute;n atribuida a los carpines dorados.