What Should a Psychiatrist Know About Genetics? Review and Recommendations From the Residency Education Committee of the International Society of Psychiatric Genetics.

The International Society of Psychiatric Genetics (ISPG) created a Residency Education Committee with the purpose of identifying key genetic knowledge that should be taught in psychiatric training programs. Thirteen committee members were appointed by the ISPG Board of Directors, based on varied training, expertise, gender, and national origin. The Committee has met quarterly for the past 2 years, with periodic reports to the Board and to the members of the Society. The information summarized includes the existing literature in the field of psychiatric genetics and the output of ongoing large genomics consortia. An outline of clinically relevant areas of genetic knowledge was developed, circulated, and approved. This document was expanded and annotated with appropriate references, and the manuscript was developed. Specific information regarding the contribution of common and rare genetic variants to major psychiatric disorders and treatment response is now available. Current challenges include the following: (1) Genetic testing is recommended in the evaluation of autism and intellectual disability, but its use is limited in current clinical practice. (2) Commercial pharmacogenomic testing is widely available, but its utility has not yet been clearly established. (3) Other methods, such as whole exome and whole genome sequencing, will soon be clinically applicable. The need for informed genetic counseling in psychiatry is greater than ever before, knowledge in the field is rapidly growing, and genetic education should become an integral part of psychiatric training

Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

In clinical settings, the information provided by genetic testing can explain the triggers and processes underlying clinical presentations, such as neurodevelopmental disorders, in up to one third of affected individuals. However, translating this knowledge into better and more personalized clinical management to many appears a distant target. This article presents three paradigmatic cases to exemplify how this translational effort can, at least in some instances, be undertaken today with very positive results: (a) a young girl carrying a chr. 16p11.2 duplication can be screened using targeted exams and undertake therapeutic/preventive interventions related to her genetic diagnosis; (b) a 13-year-old boy with intellectual disability and autism spectrum disorder carries a chr. 11q14.1 deletion, partly spanning the DLG2 gene important for synaptic function, and gained over 20 I.Q. points ostensibly due to carbolithium, prescribed in the absence of affective symptoms, exclusively following the pathophysiology pointed out by the genetic results; (c) a 58-year-old woman carries a COL3A1 gene variant responsible for the vascular form of Ehler–Danlos syndrome with colon rupture. Detection of this variant in six members of her extended family allows for better clinical management of the proband and targeted genetic counselling for family members at risk of this connective tissue disorder. The unprecedented flow of genetic information available today through new technologies, if interpreted in the light of current knowledge in clinical diagnosis and care of those with connective tissue disorders and neurodevelopmental disturbances, in biology and in neuropsychopharmacology, can promote better clinical and pharmacological treatment, disease surveillance, and management provided and incorporated into the clinical setting

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna

The York map as a Shanmugadhasan canonical transformation in tetrad gravity and the role of non-inertial frames in the geometrical view of the gravitational field

A new parametrization of the 3-metric allows to find explicitly a York map in canonical ADM tetrad gravity, the two pairs of physical tidal degrees of freedom and 14 gauge variables. These gauge quantities (generalized inertial effects) are all configurational except the trace ${}^3K(\tau ,\vec \sigma)$ of the extrinsic curvature of the instantaneous 3-spaces $\Sigma_{\tau}$ (clock synchronization convention) of a non-inertial frame. The Dirac hamiltonian is the sum of the weak ADM energy $E_{ADM} = \int d^3\sigma {\cal E}_{ADM}(\tau ,\vec \sigma)$ (whose density is coordinate-dependent due to the inertial potentials) and of the first-class constraints. Then: i) The explicit form of the Hamilton equations for the two tidal degrees of freedom in an arbitrary gauge: a deterministic evolution can be defined only in a completely fixed gauge, i.e. in a non-inertial frame with its pattern of inertial forces. ii) A general solution of the super-momentum constraints, which shows the existence of a generalized Gribov ambiguity associated to the 3-diffeomorphism gauge group. It influences: a) the explicit form of the weak ADM energy and of the super-momentum constraint; b) the determination of the shift functions and then of the lapse one. iii) The dependence of the Hamilton equations for the two pairs of dynamical gravitational degrees of freedom (the generalized tidal effects) and for the matter, written in a completely fixed 3-orthogonal Schwinger time gauge, upon the gauge variable ${}^3K(\tau ,\vec \sigma)$, determining the convention of clock synchronization. Therefore it should be possible (for instance in the weak field limit but with relativistic motion) to try to check whether in Einstein's theory the {\it dark matter} is a gauge relativistic inertial effect induced by ${}^3K(\tau ,\vec \sigma)$.Comment: 90 page

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of that risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortia and population based resources, we find genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both inherited and de novo variation, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in an ASD or other neuropsychiatric disorder diagnosis. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology

A polygenic burden of rare disruptive mutations in schizophrenia.

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years