Rare copy number variants have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large CNVs at several loci, including microdeletions at 1q21.1, 3q29, 15q13.3 and 22q11.2 and microduplication at 16p11.2. However, these CNVs collectively account for a small fraction of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy (...) number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 patients versus 2 of 7,431 controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. © 2011 Macmillan Publishers Limited. All rights reserved. (shrink)

Circadian rhythm abnormalities in bipolar disorder have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies. At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: (...) essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD. Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies. (shrink)

This book is a defense of modal realism; the thesis that our world is but one of a plurality of worlds, and that the individuals that inhabit our world are only a few out of all the inhabitants of all the worlds. Lewis argues that the philosophical utility of modal realism is a good reason for believing that it is true.

Counterfactuals is David Lewis' forceful presentation of and sustained argument for a particular view about propositions which express contrary to fact conditionals, including his famous defense of realism about possible worlds and his theory of laws of nature.

It is advisable to treat some sorts of discourse about fiction with the aid of an intensional operator "in such-And-Such fiction...." the operator may appear either explicitly or tacitly. It may be analyzed in terms of similarity of worlds, As follows: "in the fiction f, A" means that a is true in those of the worlds where f is told as known fact rather than fiction that differ least from our world, Or from the belief worlds of the community in (...) which the fiction originated. (shrink)

What knowledge would suffice to yield an interpretation of an arbitrary utterance of a language when such knowledge is based on evidence plausibly available to a nonspeaker of that language? it is argued that it is enough to know a theory of truth for the language and that the theory satisfies tarski's 'convention t' and that it gives an optimal fit to data about sentences held true, Under specified conditions, By native speakers.

The void is deadly. If you were cast into a void, it would cause you to die in just a few minutes. It would suck the air from your lungs. It would boil your blood. It would drain the warmth from your body. And it would inflate enclosures in your body until they burst}.

A solution to the problem of intrinsic change for enduring things should meet three conditions. It should not replace monadic intrinsic properties by relations. It should not replace the having simpliciter of properties by standing in some relation to them. It should not rely on an unexplained notion of having an intrinsic property at a time. Johnston's solution satisfies the first condition at the expense of the second. Haslanger's solution satisfies the first and second at the expense of the third.

In his note "can there be vague objects?" ("analysis", 1978), Gareth evans presents a purported proof that there can be no vague identity statements. Some readers think that evans endorses the proof and its false conclusion. Not so. His point is that those who put vagueness in the world, Rather than in language, Will have no way to fault the proof and no way to escape the false conclusion.

is the second-order theory of the part-whole relation. It can express such hypotheses about the size of Reality as that there are inaccessibly many atoms. Take a non-empty class to have exactly its non-empty subclasses as parts; hence, its singleton subclasses as atomic parts. Then standard set theory becomes the theory of the member-singleton function—better, the theory of all singleton functions—within the framework of megethology. Given inaccessibly many atoms and a specification of which atoms are urelements, a singleton function exists, (...) unique up to isomorphism. (This article is partly abridged from my Parts of Classes, partly a sequel.). (shrink)

This is the second volume of philosophical essays by one of the most innovative and influential philosophers now writing in English. Containing thirteen papers in all, the book includes both new essays and previously published papers, some of them with extensive new postscripts reflecting Lewis's current thinking. The papers in Volume II focus on causation and several other closely related topics, including counterfactual and indicative conditionals, the direction of time, subjective and objective probability, causation, explanation, perception, free will, and rational (...) decision. Throughout, Lewis analyzes global features of the world in such a way as to show that they might turn out to supervene on the spatiotemporal arrangement of local qualities. (shrink)

This volume is devoted to Lewis's work in ethics and social philosophy. Topics covered include the logic of obligation and permission; decision theory and its relation to the idea that beliefs might play the motivating role of desires; a subjectivist analysis of value; dilemmas in virtue ethics; the problem of evil; problems about self-prediction; social coordination, linguistic and otherwise; alleged duties to rescue distant strangers; toleration as a tacit treaty; nuclear warfare; and punishment. This collection, and the two preceding volumes, (...) will disseminate more widely the work of an eminent and influential contemporary philosopher. (shrink)

Epistemic Evaluation aims to explore and apply a particular methodology in epistemology. The methodology is to consider the point or purpose of our epistemic evaluations, and to pursue epistemological theory in light of such matters. Call this purposeful epistemology. The idea is that considerations about the point and purpose of epistemic evaluation might fruitfully constrain epistemological theory and yield insights for epistemological reflection. Several contributions to this volume explicitly address this general methodology, or some version of it. Others focus on (...) advancing some application of the methodology rather than on theorizing about it. The papers go on to explore the idea that purposes allow one to understand the conceptual demands on knowing, examine how purposeful epistemology might shed light on the debate between internalist and externalist epistemologies, and further develop the idea of purposeful epistemology. (shrink)

Topics in Cognitive Science, Volume 13, Issue 1, Page 128-141, January 2021.

Refutes the methodological separatists who hold that the logic of explanation and testing in the human sciences is fundamentally different than in the natural sciences, and develops complementary accounts for interpretation and explanation, ...