JI Nurnberger - Academia.edu (original) (raw)

Papers by JI Nurnberger

International Union of Biochemistry and Molecular Biology: Life, 1999

The pineal hormone melatonin regulates various neural and endocrine processes involved in mammali... more The pineal hormone melatonin regulates various neural and endocrine processes involved in mammalian circadian rhythms. To understand how melatonin mediates these functions, we investigated melatonin-like immunoreactivity (MLI) in cell extracts and human brain. In Western immunoblots, we detected highmolecular-mass protein bands (85± 135 kDa) that speci® cally reacted with the anti-melatonin antibody. The speci® c protein bands were present in cell extracts from the human brain and cell lines of different origins. The immunoreactive signal of the 135-kDa protein band was highest in a neuroendoc rine PC12 cell line, which was 10-fold higher than the signal observed in any cell extracts used. The commercial antibody employed in the Western blots was further puri® ed against serum proteins and thyroglobulins. We have previously reported that the antibody against melatonin recognizes MLI as detected by a sensitive RIA. In the present report we have detected the putative melatonin-speci® c binding proteins, which could contribute to the MLI. Our results suggest that melatonin binds with speci® c proteins in different cellular and brain extracts, the protein(s) being maximally synthesized in PC12 cells. These results may indicate a group of yet unknown proteins sharing a melatonin-like epitope or the presence of melatonin-binding protein(s) that regulate availability of free melatonin, or both.

Adherence to Treatment Regimen in a Lithium Carbonate Clinic

Archives of General Psychiatry, 1982

Adherence to a prophylactic regimen for primary affective disorder was studied with the Standardi... more Adherence to a prophylactic regimen for primary affective disorder was studied with the Standardized Compliance Questionnaire given to 48 outpatients to determine perceptions of their illness, treatment, mood state, and side effects. Clinicians rated the course of the illness for 12 months. Adherence was defined as lithium level between 0.5 and 1.5 mEq/L and attendance at 75% of clinic appointments for nine months. One patient was nonadherent with both indices, whereas 11 were nonadherent with neither medication regimen or appointment keeping, suggesting that each behavior should be scrutinized separately. Elevated mood was associated with overall nonadherence, marriage was associated with adherence to drug regimen, and perception of continuity of care was associated with appointment-keeping adherence. No association was found between nonadherence and diagnostic subcategory or between adherence and reported side effects. The relationship between nonadherence and poor outcome was significant.

Alcoholism and mania: Is there a genetic relationship?

The genetics of bipolar affective disorder

Current Opinion in Psychiatry, 2007

Bipolar affective disorder is a highly heritable condition, as demonstrated in twin, family, and ... more Bipolar affective disorder is a highly heritable condition, as demonstrated in twin, family, and adoption studies. Morbid risk in first degree relatives is four to six times higher than the population prevalence of about 1%. However, the mode of inheritance is complex, and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged on several chromosomes, notably 18p, 18q, 21q, 12q, 4p, and Xq. Two additional areas, 10p and 13q, have shown linkage in regions that appear to overlap with significant linkage findings in schizophrenia. Separate linkage studies in schizophrenia also have targeted the replicated bipolar linkages on 18p and 22q. New methods are being developed for fine mapping and candidate identification. Recent candidate gene studies include some positive results for the serotonin transporter gene on 17q and the catechol-o-methyltransferase gene on 22q. No other candidate gene studies are yet showing replicated results. A convincing demonstration for a susceptibility gene will probably require a mixture of case- control studies, family-based association methods, and pathophysiologic studies.

Bipolar disorder is an often-severe mental health disorder characterized by alternation between e... more Bipolar disorder is an often-severe mental health disorder characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 loci of small effect, pathophysiological mechanisms and much of the genetic risk remain unknown. Here, through genome sequencing and linkage and association analyses, we found that rare variants co-segregating with bipolar disorder in large multiply affected families cluster within gene networks enriched for synaptic and nuclear functions. The top variant in this analysis prioritized by statistical association, predicted deleteriousness, and network centrality was a missense variant in the gene encoding D-amino acid oxidase (DAOG131V). Heterologous expression of DAOG131V in human cells resulted in decreased DAO protein abundance and enzymatic activity. In a knock-in mouse harboring this human DAOG131V variant, DaoG130V/+, we similarly found decreased DAO protein abundance, as well ...

Journal of Studies on Alcohol, 2002

American journal of human genetics, 1996

In 22 multiplex pedigrees screened for linkage to bipolar disorder, by use of 18 markers on chrom... more In 22 multiplex pedigrees screened for linkage to bipolar disorder, by use of 18 markers on chromosome 21q, single-locus affected-sib-pair (ASP) analysis detected a high proportion (57%-62%) of alleles shared identical by descent (IBD), with P values of .049-.0008 on nine marker loci. Multilocus ASP analyses revealed locus trios in the distal region between D21S270 and D21S171, with excess allele sharing (nominal P values <.01) under two affection-status models, ASM I (bipolars and schizoaffectives) and ASM II (ASM I plus recurrent unipolars). In addition, under ASM I, the proximal interval spanned by D21S1436 and D21S65 showed locus trios with excess allele sharing (nominal P values of .03-.0003). These findings support prior evidence that a susceptibility locus for bipolar disorder is on 21q.

Hypersensitive Cholinergic Functioning in Primary Affective Illness

Advances in Behavioral Biology, 1981

Primary affective illness is characterized by two distinct mood states, depression and mania. Whi... more Primary affective illness is characterized by two distinct mood states, depression and mania. While depressed, patients typically show changes in mood (sadness, crying, feelings of worthlessness and hopelessness), physical activity (anergy, fatigue, psychomotor retardation),and sleep changes (short fragmented sleep, with decreased latency to the onset of the first REM period (8,18). While manic, patients are euphoric, hyperactive and hyposomniac.

Pro-opiomelanocortin-related peptides in cerebrospinal fluid: A study of manic-depressive disorder

Psychiatry Research, 1985

Five peptide fragments of pro-opiomelanocortin (alpha-melanocyte-stimulating hormone, beta-lipopr... more Five peptide fragments of pro-opiomelanocortin (alpha-melanocyte-stimulating hormone, beta-lipoprotin, adrenocorticotropic hormone, beta-endorphin, and the N-terminal fragment of pro-opiomelanocortin) were measured by radioimmunoassay in cerebrospinal fluid (CSF) and plasma from 31 normal volunteers and 26 euthymic lithium-treated bipolar patients (14 of whom provided a second CSF sample in the unmedicated state). With the exception of alpha-melanocyte-stimulating hormone, in the normal volunteers&amp;#39; CSF, levels of these peptides were highly correlated with one another, suggesting that: (1) some common regulatory factor may control the levels of these four peptides in CSF; and (2) CSF alpha-melanocyte-stimulating hormone is independently regulated from the other pro-opiomelanocortin products. Some of these correlations were absent in the patient groups, suggesting subtle alterations in pro-opiomelanocortin processing in manic-depressive illness. No effect of lithium on the CSF levels of these peptides was observed. No group differences were found.

Psychiatric Genetics, 2001

The informal theme of the meeting was stated on the last Ž. day by Dieter Wildenauer Bonn , who c... more The informal theme of the meeting was stated on the last Ž. day by Dieter Wildenauer Bonn , who chaired the session on Bipolar Disorder: 'Moving beyond linkage' to candidate gene or functional studies.

Neuropeptides in human cerebrospinal fluid

Life Sciences, 1985

Ten neuropeptides were measured by RIA in human cerebrospinal fluid obtained from 30 normal volun... more Ten neuropeptides were measured by RIA in human cerebrospinal fluid obtained from 30 normal volunteers. The levels of seven peptides (corticotropin releasing factor, adrenocorticotropin, vasoactive intestinal peptide, somatostatin, beta-endorphin, beta-lipotropin, and the N-terminal fragment of proopiomelanocortin) were highly, positively correlated with one another. This result is consistent with the hypothesis that cerebrospinal fluid levels of these seven peptides are a function of some common regulatory factor, such as shared release into the cerebrospinal fluid.

Vasoactive intestinal peptide and bipolar affective illness

Journal of Affective Disorders, 1985

In an attempt to evaluate the role of VIP in affective disorder, measurements of lymphocyte VIP r... more In an attempt to evaluate the role of VIP in affective disorder, measurements of lymphocyte VIP receptors, and plasma and CSF VIP levels were made in unmedicated and lithium-treated euthymic bipolars and controls. Lithium decreased plasma (P = 0.01) and CSF (P = 0.05) VIP levels and increased the affinity (decreased the KD) of the VIP lymphocyte receptor (P less than 0.01). This effect may be relevant to the psychotropic action of lithium in manic-depressive illness.

Human Molecular Genetics, 2008

Variations in OPRK1, which encodes the k-opioid receptor, are associated with the risk for alcoho... more Variations in OPRK1, which encodes the k-opioid receptor, are associated with the risk for alcohol dependence. Sequencing DNAs with higher and lower risk haplotypes revealed an insertion/deletion (indel) with a net addition of 830 bp located 1986 bp upstream of the translation start site (1389 bp upstream of the transcription start site). We demonstrated that the upstream region extending from 21647 to 210 bp or from 22312 to 210 bp (relative to the translation start site) could function as a promoter in transient transfection assays. We then determined that the presence of the indel reduced transcriptional activity by half. We used a PCR assay to genotype individuals in 219 multiplex alcohol-dependent families of European American descent for the presence or absence of this indel. Family-based association analyses detected significant evidence of association of this insertion with alcoholism; the longer allele (with the indel), which had lower expression, is associated with higher risk for alcoholism. This indel is, therefore, a functional regulatory variation likely to explain at least part of the association of OPRK1 with alcohol dependence.

Human molecular genetics, Jan 15, 2010

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known gen... more 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…

Clinical Neuropharmacology, 1984

Behavior Genetics, 1995

The locomotor activity of male mice (Mus musculus) was monitored by infrared photoelectric beams ... more The locomotor activity of male mice (Mus musculus) was monitored by infrared photoelectric beams under three lighting regimens: LD (12 h of light and 12 h of dark), DD (constant dark), and LL (constant broad-spectrum light, 10 lux). Circadian period of locomotor activity (-r) was compared among 3 inbred strains of mice, C57BL/6J (B6), BALB/c (C), and DBA/2J (D2), and 26 recombinant inbred strains BXD (B6 X D2). The-r under both continuous low-intensity light and continuous darkness varied significantly among strains. Under DD the mean-r was 23.8 h for B6, 23.7 h for D2, and 23.6 h for C. Under LL the mean-r was 25.1 h for B6, 23.9 h for D2, and 25.5 h for C. Frequency histograms of the mean-r of 26 B XD RI mouse strains (three to seven animals per strain) in either DD or LL and the difference between them, A-r, had distributions which appeared unimodal, suggesting polygenic inheritances. The narrow-sense heritability determined using 26 strains of BXD tli mice was about 55% for-r and about 38% for both T in LL and A-r. An estimated four loci contribute to the variance of'r in constant darkness and five to the variance of "r in constant low-intensity light among the strains studied. Quantitative trait locus (QTL) analysis identified several potential genetic loci associated with-r in constant darkness,-r in constant low-intensity light, and A,r. The associations of highest probability for each of these traits were the D1Nds4 locus (p < .001) on mouse chromosome 1, the D5Ncvs52 locus (p < .05) on mouse chromosome 5, and the Pmvl2 locus (p < .01) at 70 cM on mouse chromosome 5, respectively. A QTL identified for-r was associated (p < .05) with the D2NDS1 marker at 45 cM on chromosome 2 near the Ea 6 marker at 46 cM associated (p < .05) with that reported for the period of wheel running activity in seven C• RI strains (Schwartz, W.

Plasma MHPG in Rapid Cyclers and Healthy Twins

Archives of General Psychiatry, 1981

We measured plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) in 13 pairs of healthy drug-free monozy... more We measured plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) in 13 pairs of healthy drug-free monozygotic twins. High concordance for both free and conjugated MHPG suggests that plasma levels of the metabolite may reflect a heritable biological trait. In two drug-free rapidly cycling patients studied longitudinally, plasma MHPG levels reflected alterations in psychiatric state; they were significantly higher during mania than during depression. Although largely reflecting peripheral sources, plasma MHPG level as a global index of noradrenergic function may complement urinary MHPG excretion as a probe for diagnostic subgroups or pharmacologic responsiveness in psychiatric research.

Psychiatric Genetics: Applications in Clinical Practice

American Journal of Psychiatry, 2009

... Adele C. Viguera, MDGrant support: AstraZeneca, Berlex Laboratories, Eli Lilly, Forest, Glax... more ... Adele C. Viguera, MDGrant support: AstraZeneca, Berlex Laboratories, Eli Lilly, Forest, GlaxoSmithKline, Harvard Medical School&amp;#x27;s Scholars in Medicine Fellowship (Claflin Award), Janssen, NARSAD: The Mental Health Research Association, National Institute of Mental ...

American Journal of Psychiatry, 2001

Objective: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schiz... more Objective: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder. Method: The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees.