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

The Evolution of Circumstellar Disks in Ophiuchus Binaries

Four Ophiuchus binaries, two Class I systems and two Class II systems, with separations of ~450-1100 AU, were observed with the Owens Valley Radio Observatory (OVRO) millimeter interferometer. In each system, the 3 mm continuum maps show dust emission at the location of the primary star, but no emission at the position of the secondary. This result is different from observations of less evolved Class 0 binaries, in which dust emission is detected from both sources. The nondetection of secondary disks is, however, similar to the dust distribution seen in wide Class II Taurus binaries. The combined OVRO results from the Ophiuchus and Taurus binaries suggest that secondary disk masses are significantly lower than primary disk masses by the Class II stage, with initial evidence that massive secondary disks are reduced by the Class I stage. Although some of the secondaries retain hot inner disk material, the early dissipation of massive outer disks may negatively impact planet formation around secondary stars. Masses for the circumprimary disks are within the range of masses measured for disks around single T Tauri stars and, in some cases, larger than the minimum mass solar nebula. More massive primary disks are predicted by several formation models and are broadly consistent with the observations. Combining the 3 mm data with previous 1.3 mm observations, the dust opacity power-law index for each primary disk is estimated. The opacity index values are all less than the scaling for interstellar dust, possibly indicating grain growth within the circumprimary disks

Evolution of Cold Circumstellar Dust Around Solar-Type Stars

We present submillimeter (CSO 350um) and millimeter (SEST 1.2 mm, OVRO 3 mm) photometry for 125 solar-type stars from the FEPS Spitzer Legacy program that have masses between ~0.5 and 2.0 Msun and ages from 3 Myr to 3 Gyr. Continuum emission was detected toward four stars with a signal to noise ratio >= 3$: the classical T Tauri stars RX J1842.9-3532, RX J1852.3-3700, and PDS 66 with SEST, and the debris disk system HD 107146 with OVRO. RXJ1842.9-3532 and RXJ1852.3-3700 are located in projection nearby the R CrA molecular cloud with estimated ages of ~10 Myr, while PDS66 is a probable member of the 20 Myr old Lower Centaurus-Crux subgroup of the Sco-Cen OB association. The continuum emission toward these three sources is unresolved at the 24'' SEST resolution and likely originates from circumstellar accretion disks, each with estimated dust masses of ~5x10**-5 Msun. Analysis of the visibility data toward HD107146 (age 80-200 Myr) indicates that the 3 mm continuum emission is centered on the star within the astrometric uncertainties and resolved with a gaussian-fit FWHM size of (6.5'' +/- 1.4'') x (4.2''+/-1.3''), or 185 AUx120 AU. The results from our continuum survey are combined with published observations to quantify the evolution of dust mass with time by comparing the mass distributions for samples with different stellar ages. The frequency distribution of circumstellar dust masses around solar-type stars in the Taurus molecular cloud (age ~2 Myr) is distinguished from that around 3-10 Myr and 10-30 Myr old stars at a significance level of ~1,5sigma and 3sigma respectively. These results suggest a decrease in the mass of dust contained in small dust grains and/or changes in the grain properties by stellar ages of 10-30 Myr, consistent with previous conclusions. (abridged)Comment: 37 pages, 8 figures, accepted for publication in the Astronomical Journa

Interhemispheric white matter integrity in young people with bipolar disorder and at high genetic risk

White matter (WM) impairments have been reported in patients with bipolar disorder (BD) and those at high familial risk of developing BD. However, the distribution of these impairments has not been well characterized. Few studies have examined WM integrity in young people early in the course of illness and in individuals at familial risk who have not yet passed the peak age of onset. WM integrity was examined in 63 BD subjects, 150 high-risk (HR) individuals and 111 participants with no family history of mental illness (CON). All subjects were aged 12 to 30 years. This young BD group had significantly lower fractional anisotropy within the genu of the corpus callosum (CC) compared with the CON and HR groups. Moreover, the abnormality in the genu of the CC was also present in HR participants with recurrent major depressive disorder (MDD) (n = 16) compared with CON participants. Our findings provide important validation of interhemispheric abnormalities in BD patients. The novel finding in HR subjects with recurrent MDD – a group at particular risk of future hypo/manic episodes – suggests that this may potentially represent a trait marker for BD, though this will need to be confirmed in longitudinal follow-up studies

Discovery of a Massive Protostar near IRAS 18507+0121

We have observed the massive star forming region, IRAS 18507+0121, at millimeter wavelengths in 3 mm continuum emission and H13CO+(J=1-0) and SiO(v=0, J=2-1) line emission, and at near-infrared wavelengths between 1.2 and 2.1 microns. Two compact molecular cores are detected: one north and one south separated by about 40". The northern molecular core contains a newly discovered, deeply embedded, B2 protostar surrounded by several hundred solar masses of warm gas and dust, G34.4+0.23 MM. Based on the presence of warm dust emission and the lack of detection at near-infrared wavelengths, we suggest that G34.4+0.23 MM may represent the relatively rare discovery of a massive protostar (e.g. analogous to a low-mass "Class 0" protostar). The southern molecular core is associated with a near-infrared cluster of young stars and an ultracompact (UC) HII region, G34.4+0.23, with a central B0.5 star. The fraction of near-infrared stars with excess infrared emission indicative of circumstellar material is greater than 50% which suggests an upper limit on the age of the IRAS 18507+0121 star forming region of 3 Myrs.Comment: Astrophysical Journal, in press. 21 pages plus 6 figures (jpg format). See http://www.aoc.nrao.edu/~dshepher/science.shtml for reprint with full resolution figure

Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing

High Resolution Submillimeter Constraints on Circumstellar Disk Structure

We present a high spatial resolution submillimeter continuum survey of 24 circumstellar disks in the Tau-Aur and Oph-Sco star formation regions using the SMA. In the context of a simple model, we use broadband SEDs and submillimeter visibilities to derive constraints on some basic parameters that describe the structure of these disks. For the typical disk in the sample we infer a radial surface density distribution \Sigma ~ r^-p with a median p ~ 0.5, although consideration of the systematic effects of some of our assumptions suggest that steeper distributions with p ~ 0.7-1.0 are more reasonable. The distribution of the outer radii of these disks shows a distinct peak at R_d = 200 AU, with only a few cases where the disk emission is completely unresolved. Based on these disk structure measurements, the mass accretion rates, and the typical spectral and spatial distributions of submillimeter emission, we show that the observations are in good agreement with similarity solutions for steady accretion disks that have a viscosity parameter alpha ~ 0.01. We provide new estimates of the spectral dependence of the disk opacity with a median spectral index of ~0.7, corrected for optically thick emission. This typical value is consistent with model predictions for the collisional growth of solids to millimeter size scales in the outer disk. Although direct constraints on planet formation in these disks are not currently available, the extrapolated density distributions inferred here are substantially shallower than those calculated based on the solar system or extrasolar planets and typically used in planet formation models. It is possible that we are substantially underestimating disk densities due to an incomplete submillimeter opacity prescription.Comment: submitted to ApJ (8/22/06

Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case–control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 × 10−7) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the''Guard-Hypothesis,'' R proteins (the ``guards'') can sense modification of target molecules in the host (the ``guardees'') by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the ``guardee-effector'' interface for pathogen recognition, natural selection acts on the ``guard-guardee'' interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen