Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC

A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence

Optimal energy supply network determination and life cycle analysis for hybrid coal, biomass, and natural gas to liquid (CBGTL) plants using carbon-based hydrogen production

A mixed-integer linear optimization formulation is developed to analyze the United States energy supply chain network for the hybrid coal, biomass, and natural gas to liquids (CBGTL) facilities. Each state is discretized into octants and each octant centroid serves as a potential location of one facility. The model selects the optimal locations of CBGTL facilities, the feedstock combination, and size of each facility that gives the minimum overall production cost. Two case studies are presented to investigate the effects of various technologies and hydrogen prices. The CBGTL network is capable to supply transportation fuel demands for the country at a cost between $15.68 and$22.06/GJ LHV ($76.55-$112.91/bbl crude oil) of produced liquid fuels for both case studies. Life cycle analysis on each facility in the supply chain network shows that the United States fuel demands can be fulfilled with an excess of 50% emissions reduction compared to petroleum based processes. (C) 2011 Elsevier Ltd. All rights reserved

Biomass and Natural Gas to Liquid Transportation Fuels: Process Synthesis, Global Optimization, and Topology Analysis

An optimization-based process synthesis framework is proposed for the thermochemical conversion of biomass and natural gas to liquid fuels (BGTL). Hydrocarbons are produced from synthesis gas either directly via Fischer–Tropsch synthesis or indirectly via catalytic conversion of methanol over ZSM-5. Different conversion technologies are investigated to examine their economic effects on BGTL refineries that produce gasoline, diesel, and kerosene. The process synthesis framework includes simultaneous heat, power, and water integration and utilizes a rigorous deterministic global optimization strategy to mathematically guarantee the minimal cost of the BGTL refineries. The refineries have at least 50% less life-cycle CO₂ emissions than a standard petroleum-based refinery. Forty-eight case studies are presented to determine the effect of refinery capacity, liquid fuel composition, and biomass feedstock on the overall cost, topological design, material/energy balances, and life-cycle greenhouse gas emissions. Results suggest that these systems can be economically competitive with petroleum-based processes while achieving the 50% emissions reduction

Ind. Eng. Chem. Res.

The thermochemical conversion of coal and biomass to liquid transportation fuels from a synthesis gas intermediate is investigated using an optimization-based process synthesis framework. Two distinct types of coal (LV bituminous and coal commonly found in the province of Anhui, China) and two types of biomass (hardwood and duckweed) are considered as feedstocks. The superstructure incorporates alternative conversion pathways of synthesis gas which include methanol formation and conversion into FischerTropsch hydrocarbons. Methanol may be converted to gasoline or olefins, and the olefins may be subsequently converted to gasoline and distillate. A rigorous deterministic global optimization branch-and-bound framework is utilized to determine the optimal process topology that produces liquid fuels at the lowest possible cost. Economies of scale are evident as the refinery capacity increases and it is observed that the fuel ratios of the final liquid products have a significant impact on the optimal topology of the plant. The results suggest that liquid fuels production from coal and biomass can be competitive with petroleum-based processes.The thermochemical conversion of coal and biomass to liquid transportation fuels from a synthesis gas intermediate is investigated using an optimization-based process synthesis framework. Two distinct types of coal (LV bituminous and coal commonly found in the province of Anhui, China) and two types of biomass (hardwood and duckweed) are considered as feedstocks. The superstructure incorporates alternative conversion pathways of synthesis gas which include methanol formation and conversion into FischerTropsch hydrocarbons. Methanol may be converted to gasoline or olefins, and the olefins may be subsequently converted to gasoline and distillate. A rigorous deterministic global optimization branch-and-bound framework is utilized to determine the optimal process topology that produces liquid fuels at the lowest possible cost. Economies of scale are evident as the refinery capacity increases and it is observed that the fuel ratios of the final liquid products have a significant impact on the optimal topology of the plant. The results suggest that liquid fuels production from coal and biomass can be competitive with petroleum-based processes