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The rapid progress in psychiatric genetics over the past 10 years, while exciting from a research perspective, has not yet had an impact on clinical practice. How will we really be able to put genetics to work in the psychiatric clinic? This overview will attempt to answer this question. A survey of widely used methods and major study designs highlights key findings that have emerged so far. These findings inform a broad conceptual model of how genetic risk may act to influence dimensions of psychopathology and clinical presentations. The overview concludes with highlights of some of the most clinically relevant findings to date and their implications for psychiatric practice in the near future.

BackgroundGenome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants.MethodsWe sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n=1,672).ResultsOur analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n=314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1.ConclusionsOur findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.

Background Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. Methods We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1370 controls and 2006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). Results The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT (p=8.9×10−8 for rs4854912) with a secondary peak in the adjacent FXR1 gene (p=1.2×10−6 for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis (p=3.5×10−7 and 4.3×10−6, respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. Limitations While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. Conclusions These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness.

BACKGROUND: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). RESULTS: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. CONCLUSIONS: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS. Verena Zuber is supported by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z) and the UK Medical Research Council (Grant Number MC_UU_00002/7).

Funding: SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders,University of Bergen, Bergen, Norway, the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 602805 and NIMH grants R13MH059126 and R01MH094469. JRK is supported by NIH grants MH078151, MH081804, MH59567 and MH094483. AR is supported by the Deutsche Forschungsgemeinschaft (KFO 125, TRR 58/B06 and Z02 to AR, RE1632/5-1, RTG 1256 AR) and the European Community‘s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 602805 (“AGGRESSOTYPE”). CJS and HW are supported by Interdisziplinäres Zentrum für Klinische Forschung (IZKF) grant Z-6. The research leading to these results also received funding from the European Community’s Seventh Framework Programme (FP7/2007 –2013) under grant agreements n° 602805 (AGGRESSOTYPE), n° 278948 (TACTICS), and n° 60245 (IMAGEMEND) and from the European Community’s Horizon 2020 Programme (H2020/2014 –2020) under grant agreement n° 643051 (MiND) and n° 667302( CoCA). In addition, their work is supported by the ECNP for the Research Network ‘ADHD across the Lifespan’. Background Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD. Methods Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks. Results We found a significant single nucleotide polymorphism–based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull =.64, p = 3.13 × 10–14; rGrestricted =.71, p = 4.09 × 10–16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10–8; prs11756438 = 4.36 × 10–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue. Conclusions The single nucleotide polymorphism–based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset. Postprint

Background A disrupted circadian clock has been linked to the risk of several neuropsychiatric disorders. Likewise, circadian rhythms have been suggested as mediators of the mechanism of action of lithium in bipolar disorder. Nonetheless the relationship between the ‘clock genes’ that regulate circadian rhythms and lithium treatment response is not completely understood. To our knowledge there has not been a systematic pathway / enrichment analysis of clock genes in the context of psychiatric traits, in general, and of clinical response to lithium, in particular. The objective of this study was to perform formal gene set enrichment analyses for circadian clock genes, using publicly available GWAS summary statistics from several psychiatric disorders, as well as the results from The International Consortium on Lithium Genetics (ConLiGen) GWAS (Hou et al., 2016). Methods Based on previous literature (Pizarro et al., 2013; Chen et al., 2016) and available resources (e.g. http://circadb.hogeneschlab.org/) curated gene sets related to circadian control were generated. These sets can be divided in three categories: clock modulator (upstream) genes, core clock genes and clock controlled (downstream) genes. GWAS summary statistics from schizophrenia, bipolar disorder, major depressive disorder, ADHD, autism, Alzheimer's disease and continuous/dichotomous lithium response were used as reference. Gene set enrichment analyses were carried out using both INRICH and MAGMA. Results Gene set enrichment analyses using INRICH and MAGMA reported a significant enrichment of a set of 19 genes that constitute the ‘core clock’ in the dichotomous lithium response phenotype (INRICH: empirical P=0.001; corrected P=0.008; MAGMA: competitive P=0.005; corrected P=0.0336). None of the circadian gene sets showed a significant enrichment in any of the other psychiatric traits included in this study (all corrected P>0.05). Discussion Our results suggest the involvement of those genes that constitute the core clock machinery in the determination of the clinical response to lithium in bipolar disorder patients. The specificity of these results suggests that the participation of circadian rhythms is especially relevant in the modulation of lithium response rather than in the overall risk of mental illness. A better understanding of potential links between circadian mechanisms, genetic risk factors, and the lithium treatment response may open new avenues into the clinical management of bipolar disorder.

YWHAH is a positional and functional candidate gene for both schizophrenia and bipolar disorder (BP). This gene has been previously shown to be associated with both disorders, and the chromosome location (22q12.3) has been repeatedly implicated in linkage studies for these disorders. It codes for the η subtype of the 14-3-3 protein family, is expressed mainly in brain, and is involved in HPA axis regulation. We investigated the association of YWHAH with BP in a large sample, consisting of 1211 subjects from 318 nuclear families including 554 affected offspring. We tested for association with the standard BP phenotype as well as subtypes defined by psychotic and mood-incongruent features. We genotyped five tag SNPs and the (GCCTGCA)n polymorphic locus present in this gene. Using a family-based association test, we found that rs2246704 was associated with BP (OR 1.31, P = 0.03) and psychotic BP (OR = 1.66, P = 0.002). The polymorphic repeat and two other SNPs were also modestly associated with psychotic BP. We have provided additional evidence for association of variants in YWHAH with major mental illness. Additional association analyses of larger sample sets will be required to clarify the role of YWHAH in schizophrenia and BP. The use of clinical sub-phenotypes such as psychotic features or other potential schizophrenia/BP overlap variables including cognitive abnormalities and poor functioning might shed further light on the potential subtypes of illness most closely associated with genetic variation in YWHAH. © 2009 Wiley-Liss, Inc.

The use of clinical features to define subtypes of a disorder may aid in gene identification for complex diseases. In particular, clinical subtypes of mania may distinguish phenotypic subgroups of bipolar subjects that may also differ genetically. To assess this possibility, we performed a genome-wide association study using genotype data from the Bipolar Genome Study (BiGS) and subjects that were categorized as having either irritable or elated mania during their most severe episode. A bipolar case-only analysis in the GAIN bipolar sample identified several genomic regions that differed between irritable and elated subjects, the most significant of which was for 33 SNPs on chromosome 13q31 (peak p = 2×10(-7)). This broad peak is in a relative gene desert over an unknown EST and between the SLITRK1 and SLITRK6 genes. Evidence for association to this region came predominantly from subjects in the sample that were originally collected as part of a family-based bipolar linkage study, rather than those collected as bipolar singletons. We then genotyped an additional sample of bipolar singleton cases and controls, and the analysis of irritable vs. elated mania in this new sample did not replicate our previous findings. However, this lack of replication is likely due to the presence of significant differences in terms of clinical co-morbity that were identified between these singleton bipolar cases and those that were selected from families segregating the disorder. Despite these clinical differences, analysis of the combined sample provided continued support for 13q31 and other regions from our initial analysis. Though genome-wide significance was not achieved, our results suggest that irritable mania results from a distinct set of genes, including a region on chromosome 13q31.

In a study of 471 bipolar disorder (BD) cases and 1761 controls, individuals with BD were 6.8 times more likely to report a lifetime history of cannabis use. Rates of DSM-IV cannabis use disorders in those with BD were 29.4% and were independently and significantly associated with increased suicide attempts, greater likelihood of mixed episodes and greater disability attributable to BD.

IMPORTANCE: Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders.OBJECTIVE: To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS).DATA SOURCES: Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data.STUDY SELECTION: The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample.DATA EXTRACTION AND SYNTHESIS: We identified 966 genes that contained 2 or more variants associated with BP at P MAIN OUTCOMES AND MEASURES: Empirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P CONCLUSIONS AND RELEVANCE: Pathways involved in the genetic predisposition to BP include hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicate neuronal development pathways as well. These results tend to reinforce specific hypotheses regarding BP neurobiology and may provide clues for new approaches to treatment and prevention.

Nutrient modulation increases mouse neuroblastoma (NB) T 4 -5′-deiodinase II (T 4 -5′-D II) activity. Carbohydrates are more potent than either amino acids or glycerol as nutrient sources. Glucose rapidly (2 to 4 hours) enhances NB enzyme activity and the response is dependent on new protein synthesis. The present study was performed to further characterize this glucose effect and explore its relationship to the cyclic adenosine monophosphate (cAMP) system in these cells. NB T 4 -5′-D II activity reached a maximum level (sixfold) in response to glucose (10 mmol/L) at 16 hours and thereafter remained constant up to 22 hours before reverting back to basal level between 24 and 30 hours. This pattern of response allowed the performance of detailed studies on maximum glucose activated NB T 4 -5′-D II under transient equilibrium conditions during the 16- to 22-hour period. Addition of dibutyryl cAMP (dbcAMP) (1 mmol/L) at this stage significantly increased enzyme activity (twofold at 2 hours and fourfold at 4 and 6 hours) compared with glucose alone. There was an additive response to dbcAMP under these maximum glucose-activated conditions. Nonactivated NB T 4 -5′-D II showed a twofold response to dbcAMP (1 mmol/L) at 4 hours in a glucose-free medium. Under these conditions, glucose (10 mmol/L) also increased enzyme activity twofold. Combined studies with dbcAMP and glucose increased enzyme activity fourfold at 4 hours. Subsequent studies were performed with forskolin (10 μmol/L) and cholera toxin (1 nmol/L), modulators of endogenous cAMP. The maximum enzyme response (2.5-fold) to forskolin was noted at 6 hours, whereas the peak effect of cholera toxin (twofold) occurred at 4 hours. Puromycin (100 μmol/L) decreased enzyme activity in the glucose-activated NB cell preparations at 2 hours (to 30% of control) and at 6 hours (to 50% of control). Coincubations (pre- and postpuromycin) with dbcAMP did not alter the puromycin effect at 2 and 4 hours. Actinomycin-D (1 μmol/L) did not alter NB T 4 -5′-D II activity in the glucose-activated cells at either 2 or 4 hours postaddition, but did block the dbcAMP-induced increase in enzyme activity at 4 hours. Thus, mouse neuroblastoma T 4 -5′-D II is responsive to cAMP modulation. The enzyme response to dbcAMP is not dependent on glucose, but is mediated by new protein synthesis. The responses to dbcAMP and glucose are additive. Thus, the glucose stimulation of brain T 4 -5′-D II is not dependent on an increase in intracellular cAMP. The additive effects of glucose and dbcAMP suggest different mechanisms for the enhancement of neuroblastoma T 4 -5′-D II activity.

Fever in children is a common problem, but one which often alarms parents. Parental misconceptions often lead them to unnecessarily aggressive and inappropriate management of fever in their children. A prospective controlled trial of an educational intervention to improve parental understanding and management of fever, involving the parents of 108 children, aged 6 months to 4 years, was performed in a private group practice. Although the majority of these patients were well educated, most were found to be misinformed about many aspects of the seriousness of fever and its management. Parents in the intervention group received a standardized interview in which the management of fever was discussed, demonstrated, and practiced. In addition, they received a printed information sheet for reinforcement 2 months after the initial interview. Parents in both the control group and intervention group revealed an increase in knowledge about fever over time, but only in the intervention group were inappropriate physician contacts and medication errors reduced. The effectiveness of an active learning approach to anticipatory guidance for the management of transient febrile illness was documented and it is suggested that extension of this approach to other common problems in the private practice setting be examined.

Functional lipoprotein lipase activity was recently described in rat brain. The present study was performed to further characterize the biologic significance of brain lipoprotein lipase (heparin releasable component) and elucidate regulatory factors. Comparative studies were performed on tissue (brain, adipose, and heart) heparin releasable lipoprotein lipase in the fasted and diabetic (streptozotocin 100 mg/kg BW IP) rat. Both fasting (96 hours) and diabetes (ten days) significantly decreased brain (cortical) (P < .05) and adipose (epididymal fat pad) (P < .001) lipoprotein lipase activity. In contrast, heart muscle enzyme activity was significantly increased (P < .001) in response to fasting and diabetes. Refeeding (Purina chow 96 hours) and insulin replacement (96 hours) reversed these changes in tissue lipoprotein lipase consequent to fasting and diabetes, respectively. There was a positive correlation between the changes in serum insulin concentration and adipose lipoprotein lipase, but there was no correlation between this parameter and brain or heart lipoprotein lipase. In addition, although T3 therapy normalized the low T3 state associated with both fasting and diabetes, it had no effect on the enzyme activity in the studied tissues. However, subsequent studies demonstrated that hypothyroidism (2 weeks post thyroidectomy) significantly decreased brain lipoprotein lipase activity (P < .001) and increased both the adipose (P < .025) and heart (P < .025) enzyme activity. T3 replacement (0.8 μg100 BW/d for 1 week) reversed the effects of hypothyroidism. However, the relationship between brain enzyme activity and serum T3 was nonlinear as hyperthyroidism tended to reduce brain LPL activity. These studies demonstrate that rat cortex heparin releasable lipoprotein lipase is responsive to fasting, diabetes, and hypothyroidism. Although both insulin and T3 reversed, respectively, the effects of diabetes and hypothyroidism on cortex LPL, confirmation of direct hormone effects on enzyme activity must await future in vitro studies. The brain and adipose LPL response to fasting and diabetes was concordant, whereas the effect of hypothyroidism on the respective enzymatic responses was discordant. This study does indicate that cortical lipoprotein lipase could play an important role in brain lipid metabolism.

As many as 15% of cases of systemic infection with Cryptococcus neoformans have cutaneous involvement. The existence of primary cutaneous disease is controversial. We report a patient with cutaneous cryptococcosis without evidence of visceral involvement at the time of diagnosis. She has been followed up for 5 years and remains free of systemic involvement. Cutaneous cryptococcosis does not always signify systemic disease.

The glucose-fed rat, in contrast to the chow-fed animal, has a higher serum total T3 concentration and an increase in the hepatic content of T4 5'-deiodinase (type I) activity. The mechanism and significance of these glucose-induced changes in T3 metabolism are elucidated in this study. To focus on extrathyroidal thyroid hormone metabolism the kinetic parameters were determined in thyroidectomized T4-replaced rats (1.25 micrograms T4/100 g BW.day). Kinetics of T4 and T3 were studied separately by infusing labeled hormone to equilibrium. Glucose feeding for 72 h (G) significantly increased both the total and free serum T3 concentrations compared to the respective means in the chow-fed control group (P). The glucose-induced changes in serum T3 reflect the approximate doubling of T3 production to 14.7 +/- 0.6 ng/h.100 g in G rats compared to 7.6 +/- 0.7 ng/h.100 g in P rats. The higher T3 production rate in the G group is due to a significant increase in the fractional total body T4 to T3 conversion (0.33 +/- 0.02) compared to that in the P group (0.19 +/- 0.02). The tissue (liver, kidney, brain, and brown adipose tissue) concentration of T4 (nanograms per g wet wt) was significantly increased in the G group. The increase ranged from 54% in liver to 80% in kidney, brain, and brown adipose tissue. The tissue concentration of T3 (nanograms per g wet wt) was even more dramatically increased by glucose feeding than was T4. The glucose-induced increment in organ T3 ranged from 2.5-fold (kidney, muscle, and brain) to 5-fold (liver and white adipose tissue) to 12-fold (brown adipose tissue). These data indicate that the increase in serum total and free T3 concentrations associated with glucose feeding reflects augmented total body T3 production from T4. The effect of the enhanced T3 neogenesis was generalized, as the T3 content was increased in each organ studied. Thus, glucose feeding has unique effects on T3 metabolism.

The T3 concentration in brain predominantly reflects local production from T4 rather than T3 uptake from the circulating pool. We recently demonstrated that rat brain T3 content is increased by glucose feeding compared to chow feeding. One possible mechanism for this effect is an increase in brain T4 5'-deiodinase (5'-D) activity. Our recent preliminary studies of neuroblastoma (NB) cells demonstrate that renewal of RPMI-1640 medium stimulates T4 5'-D type II (NB T4 5'-D II) activity in these cells. The present studies were performed to determine the mechanism of this response. Studies were performed on NB cells supported in thyroid hormone-depleted (deficient) medium. This approach increased NB T4 5'-DII activity 4-fold compared to that in thyroid hormone-replete medium. Medium renewal further stimulated enzyme activity (7- to 9-fold; maximum at 6 h) in each group. The difference between the hypothyroid group and control was sustained over a 24-h period. Subsequent studies demonstrated that glucose (11 mM) was the specific medium ingredient mediating the medium renewal response. A progressive increase in NB T4 5'-DII activity was noted over 8 h during RPMI-1640 salt plus glucose (11 mM) incubation. This was equivalent to the effect of complete medium containing glucose (11 mM). Coincubation with insulin (10(-7)-10(-9) M) did not modify the enzyme response to glucose. In addition, fructose (10 mM) had a similar effect on enzyme activity. Glycerol and essential and nonessential amino acids also modestly increased NB T4 5'-DII activity compared to that in the control group (P less than 0.01). Actinomycin-D (1 microM), cycloheximide (100 microM), and puromycin (100 microM) significantly (P less than 0.001) decreased the glucose effect on T4 5'-DII by 5-, 9-, and 17-fold, respectively, after 6 h of incubation. In addition, puromycin (10-200 microM) inhibited both NB T4 5'-DII activity and [3H]amino acid incorporation during incubation in glucose. There was a significant correlation between these parameters (r = 0.8; P less than 0.001). The enzyme activity decay curves in the glucose-activated and control groups subsequent to puromycin (100 microM) addition at 8 h were parallel. The fractional turnover rate was 13%/h in the controls and 11%/h in the glucose groups. The calculated enzyme production rate was significantly higher (P less than 0.005) in the glucose group compared to that in the control group (17.4 vs. 6.8 fmol/mg protein.h).(ABSTRACT TRUNCATED AT 400 WORDS)

Fever in children is a common problem, but one which often alarms parents. Parental misconceptions often lead them to unnecessarily aggressive and inappropriate management of fever in their children. A prospective controlled trial of an educational intervention to improve parental understanding and management of fever, involving the parents of 108 children, aged 6 months to 4 years, was performed in a private group practice. Although the majority of these patients were well educated, most were found to be misinformed about many aspects of the seriousness of fever and its management. Parents in the intervention group received a standardized interview in which the management of fever was discussed, demonstrated, and practiced. In addition, they received a printed information sheet for reinforcement 2 months after the initial interview. Parents in both the control group and intervention group revealed an increase in knowledge about fever over time, but only in the intervention group were inappropriate physician contacts and medication errors reduced. The effectiveness of an active learning approach to anticipatory guidance for the management of transient febrile illness was documented and it is suggested that extension of this approach to other common problems in the private practice setting be examined.

This report focuses on the design and development of a pressure sensitive cell and the use of this cell in making pressure measurements in homogeneous and two-layer model pavement systems. Pressures were measured under three different size plates, on a homogeneous compacted clay fill, and on the same fill when varying thicknesses of the upper portion of the clay had been replaced with a compacted crushed limestone base. These measured pressures have been compared with the theoretical pressures, as determined by the Boussinesq and the Burmister Methods. They have also been compared with pressure measurements made by the Corps of Engineers, at their Waterways Experiment Station. A fair correlation of measured and theoretical pressures has been made by using a modification of the Boussinesq method, called the Equivalent Plate Method. However, it is necessary to have the magnitude of the interface pressure to establish this correlation.

The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017).In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.

A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The affected-sibpair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37: 64% in bipolar and recurrent unipolar (RUP) sib pairs (P = .0006). In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q: at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = 0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.e., those in which the father or one of the father's sibs is affected. In these pedigrees, the greatest allele sharing (81%; P = .00002) and the highest LOD score (3.51; phi = 0.0) were observed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder. The number of loci involved, and their precise location, require further study..

Experimental evidence for the formation of Ti3B4 with an orthorhombic Ta3B4-type structure is presented. This phase forms by a peritectic reaction between TiB2 and liquid at ∼2200°C and is stable to temperatures at least as low as 1690°C, the lowest temperature at which samples were annealed. No evidence was found to indicate the presence of a second high-temperature form of this phase, as has been reported in the literature.