Kyra Kanyas

Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia

The low-to-moderate resolution of linkage analysis in complex traits has underscored the need to identify disease phenotypes with presumed genetic homogeneity. Bipolar disorder (BP) accompanied by psychosis (psychotic BP) may be one such phenotype. We previously reported a genome-wide screen in a large bipolar pedigree sample. In this follow-up study, we reclassified the disease phenotype based on the presence or absence of psychotic features and subgrouped pedigrees according to familial load of psychosis. Evidence for significant linkage to psychotic BP (genome-wide P<0.05) was obtained on chromosomes 9q31 (lod=3.55) and 8p21 (lod=3.46). Several other sites were supportive of linkage, including 5q33 (lod=1.78), 6q21 (lod=1.81), 8p12 (lod=2.06), 8q24 (lod=2.01), 13q32 (lod=1.96), 15q26 (lod=1.96), 17p12 (lod=2.42), 18q21 (lod=2.4), and 20q13 (lod=1.98). For most loci, the highest lod scores, including those with genome-wide significance (at 9q31 and 8p21), occurred in the subgroup of families with the largest concentration of psychotic individuals (≥3 in a family). Interestingly, all regions but six—5q33, 6q21, 8p21, 8q24, 13q32 and 18q21—appear to be novel; namely, they did not show notable linkage to BP in other genome scans, which did not employ psychosis for disease classification. Also of interest is possible overlap with schizophrenia, another major psychotic disorder: seven of the regions presumed linked in this study—5q, 6q, 8p, 13q, 15q, 17p, and 18q—are also implicated in schizophrenia, as are 2p13 and 10q26, which showed more modest support for linkage. Our results suggest that BP in conjunction with psychosis is a potentially useful phenotype that may: (1) expedite the detection of susceptibility loci for BP and (2) cast light on the genetic relationship between BP and schizophrenia.

Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorder

We conducted a 9-cM genome scan in a large bipolar pedigree sample from the National Institute of Mental Health genetics initiative (1060 individuals from 154 multiplex families). We performed parametric and nonparametric analyses using both standard diagnostic models and comorbid conditions thought to identify phenotypic subtypes: psychosis, suicidal behavior, and panic disorder. Our strongest linkage signals (genome-wide significance) were observed on chromosomes 10q25, 10p12, 16q24, 16p13, and 16p12 using standard diagnostic models, and on 6q25 (suicidal behavior), 7q21 (panic disorder) and 16p12 (psychosis) using phenotypic subtypes. Several other regions were suggestive of linkage, including 1p13 (psychosis), 1p21 (psychosis), 1q44, 2q24 (suicidal behavior), 2p25 (psychosis), 4p16 (psychosis, suicidal behavior), 5p15, 6p25 (psychosis), 8p22 (psychosis), 8q24, 10q21, 10q25 (suicidal behavior), 10p11 (psychosis), 13q32 and 19p13 (psychosis). Over half the implicated regions were identified using phenotypic subtypes. Several regions – 1p, 1q, 6q, 8p, 13q and 16p – have been previously reported to be linked to bipolar disorder. Our results suggest that dissection of the disease phenotype can enrich the harvest of linkage signals and expedite the search for susceptibility genes. This is the first large-scale linkage scan of bipolar disorder to analyze simultaneously bipolar disorder, psychosis, suicidal behavior, and panic disorder.

Evidence for a putative bipolar disorder locus on 2p13-16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21-24, 13q32, 14q21 and 17q11-12.

Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide P<0.05) for markers on 2p13–16. Standard linkage analysis was also supportive of linkage to 2p13–16 (lod=3.20), and identified several other interesting regions: 4q31 (lod=3.16), 7q34 (lod=2.78), 8q13 (lod=2.06), 9q31 (lod=2.07), 10q24 (lod=2.79), 13q32 (lod=2.2), 14q21 (lod=2.36) and 17q11–12 (lod=2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13–16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21–24, 13q32 and 17q11–12). Two of the regions implicated in our study, 2p13–14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common.

Further evidence for a susceptibility locus on chromosome 10p14-p11 in 72 families with Schizophrenia by nonparametric linkage analysis

Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage. We obtained highest allele sharing for the two markers D10S582 (61.5% allele sharing, chi2 = 7.6, P = 0.0058) and D10S1423 (59% allele sharing, chi2 = 4.76, P = 0.029). D10S1423 is one of the markers with the highest lod scores in the study of Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557]. GENEHUNTER analysis revealed a nonparametric lod score (NPL) of 3.2 (P = 0.0007) for the marker D10S1714, which lies in the same region. Multipoint affected sib-pair lod score analysis (identity by descent) calculated by ASPEX revealed a lod score of 1.72 for all possible sib-pair combinations (107) and of 2.13, when only independent sib-pairs (87) were counted. Our study provides further evidence for a potential susceptibility locus for schizophrenia on chromosome 10p.

Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes.

Despite the health hazards, cigarette smoking is disproportionately frequent among young women. A significant contribution of genetic factors to smoking phenotypes is well established. Efforts to identify susceptibility genes do not generally take into account possible interaction with environment, life experience and psychological characteristics. We recruited 501 female Israeli students aged 20–30 years, obtained comprehensive background data and details of cigarette smoking and administered a battery of psychological instruments. Smoking initiators (n=242) were divided into subgroups with high (n=127) and low (n=115) levels of nicotine dependence based on their scores on the Fagerstrom Tolerance Questionnaire and genotyped with noninitiators (n=142) for single nucleotide polymorphisms (SNPs) in 11 nicotinic cholinergic receptor genes. We found nominally significant (P<0.05) allelic and genotypic association with smoking initiation of SNP rs2072660 and multilocus haplotypes (P<0.007–0.05) in CHRNB2 and nominal (P<0.05) allelic or genotypic association of SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) with nicotine dependence. Employing logistic regression and controlling for known risk factors, the best-fitting model for smoking initiation encompassed a 5 SNP haplotype in CHRNB2, neuroticism and novelty seeking (P=5.9 × 10−14, Nagelkerke r2=0.30). For severity of nicotine dependence, two SNPs in CHRNA7 (rs1909884 and rs883473), one SNP in CHRNA5 (rs680244) and the interaction of a SNP in CHRNA7 (rs2337980) with neuroticism, were included in the model (P=2.24 × 10−7, Nagelkerke r2=0.40). These findings indicate that background factors, psychological characteristics and genetic variation in nicotinic cholinergic receptors contribute independently or interactively to smoking initiation and to severity of nicotine dependence in young women.

Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24

Schizophrenia is a complex neuropsychiatric disorder to which an as-yet-unknown number of genes contribute, interacting with each other and the environment. Linkage analyses have implicated several chromosomal regions as harboring schizophrenia susceptibility loci although rarely at levels commensurate with proposed thresholds for genome-wide significance. We systematically recruited Arab Israeli families multiply affected with schizophrenia from the catchment area of a Regional Mental Health Center. Clinical diagnoses were established by semistructured interviews and all other available sources of information under narrow, core and broad categories. Using 350 microsatellite markers, spaced at an average of 10.3 cM, we performed an autosomal scan in 155 subjects from 21 families. Linkage analysis employed affects only, multipoint, nonparametric (model-free) and also parametric (dominant and recessive) approaches. We detected significant evidence for a schizophrenia susceptibility gene at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) under the broad diagnostic category and a parametric LOD score of 3.33 (dominant model). Under the core diagnostic category the NPL was 4.29 (P=0.00001) and the LOD score 4.16 (dominant model). We also detected suggestive evidence for linkage at chromosome 10q24 under the broad diagnostic category (NPL 3.24, P=0.0008; heterogeneity LOD score, dominant model 2.65, α=0.82). Additionally, NPL scores >2.0 were observed at chromosome 2q37, 4p15–16, 7p22, 9q21–22 and 14q11.1–11.2. The linkage we detected at chromosome 6q23 fulfills the criteria for genome-wide significance and is located approximately midway between loci suggested by a previous significant report at chromosome 6q25 and findings located more centromerically at 6q21–22.

Association study of cannabinoid receptor gene (CNR1) alleles and anorexia nervosa: Differences between restricting and bingeing/purging subtypes

Anorexia nervosa (AN) is a severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. Family and twin studies indicate a significant genetic contribution to this disorder although no genetic mutation has yet been identified. The endocannabinoid system has recently been implicated in many physiological functions including appetite regulation. We, therefore, undertook a family based study to test the hypothesis whether a polymorphism of the CNR1 gene, which encodes human CB1 receptor, a subclass of the central cannabinoid receptor, contributes to the susceptibility to AN. Fifty two families (parents with one or two affected siblings) were genotyped for the (AAT) trinucleotide repeat of CNR1 gene. Using the haplotype relative risk (HRR) method, the distribution of alleles transmitted to the patients was not found to be significantly different from the non‐transmitted parental alleles. However, upon dividing the samples to restricting and bingeing/purging subtypes of AN, the extended transmission disequilibrium test (ETDT) revealed that there is preferential transmission of different alleles in each of the subtypes. The 14 repeat allele was preferentially transmitted in the bingeing/purging AN group (P = 0.05) but not in the restricting AN group, whereas the 13 repeat allele was preferentially transmitted in the restricting AN group (almost significant, P = 0.07) but not in the bingeing/purging AN group. Our study suggests that restricting AN and bingeing/purging AN may be associated with different alleles of the CNR1 gene.

AHI1 , a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia

Schizophrenia, a severe neuropsychiatric disorder, is believed to involve multiple genetic factors. A significant body of evidence supports a pivotal role for abnormalities of brain development in the disorder. Linkage signals for schizophrenia map to human chromosome 6q. To obtain a finer localization, we genotyped 180 single nucleotide polymorphisms (SNPs) in a young, inbred Arab-Israeli family sample with a limited number of founders. The SNPs were mostly within a ∼7 Mb region around the strong linkage peak at 136.2 Mb that we had previously mapped. The most significant genetic association with schizophrenia for single SNPs and haplotypes was within a 500 kb genomic region of high linkage disequilibrium (LD) at 135.85 Mb. In a different, outbred, nuclear family sample that was not appropriate for linkage analysis, under-transmitted haplotypes incorporating the same SNPs (but not the individual SNPs) were significantly associated with schizophrenia. The implicated genomic region harbors the Abelson Helper Integration Site 1 (AHI1) gene, which showed the strongest association signal, and an adjacent, primate-specific gene, C6orf217. Mutations in human AHI1 underlie the autosomal recessive Joubert Syndrome with brain malformation and mental retardation. Previous comparative genomic analysis has suggested accelerated evolution of AHI1 in the human lineage. C6orf217 has multiple splice isoforms and is expressed in brain but does not seem to encode a functional protein. The two genes appear in opposite orientations and their regulatory upstream regions overlap, which might affect their expression. Both, AHI1 and C6orf217 appear to be highly relevant candidate genes for schizophrenia.

Anorexia nervosa and parental bonding: the contribution of parent-grandparent relationships to eating disorder psychopathology.

The present study adopted an intergenerational approach in examining the association between parental bonding and anorexia nervosa. Forty-three anorexic participants and 33 nonclinical comparison participants completed eating disorder questionnaires and the Parental Bonding Instrument (PBI). The participants parents also completed the PBI. The anorexic participants perceived both parents as less caring and fathers as more controlling than nonclinical participants. Among anorexic participants, mother control and father care were associated with symptom severity. Intergenerational effects were present. Among anorexic participants, maternal grandmother care was associated with eating disorder psychopathology. The present findings suggest that parental characteristics of grandparents might play a role in the development of eating disorders in granddaughters.

Why do young women smoke? III. Attention and impulsivity as neurocognitive predisposing factors

Since nicotine has been shown to facilitate sustained attention and control of impulsivity, impairment in these domains may influence individuals who initiate smoking for various reasons to continue to smoke cigarettes. The purpose of this study was to determine whether young women who smoke regularly but are not abstinent at the time of testing, differ in their cognitive functioning from non-smokers and whether they resemble women who smoked in the past but quit. Female undergraduate students aged 20-30 years were recruited by advertisement from institutes of higher education in the Jerusalem area. The study sample consisted of 91 current smokers (CS), 40 past smokers (PS) and 151 non-smokers (NS). 46 occasional smokers (OS) were also tested. Confounding by withdrawal state was neutralized by including only CS and OS who smoked their last cigarette less than 90 min before testing. Subjects performed a computerized neurocognitive battery, which tests the domains of attention, memory, impulsivity, planning, information processing and motor performance. Analyses were controlled for age. The results showed that CS made significantly more errors than NS on the Continuous Performance Task (CPT), Matching Familiar Figures Test (MFFT) and Tower of London (TOL) test. PS were significantly worse than NS on the MFFT and TOL test. PS did not differ significantly from CS on any test. No association was found between duration of smoking and performance. These findings suggest that a neurocognitive profile characterized by impairments in sustained attention and control of impulsivity may be one of the factors that predispose young women who initiate cigarette smoking to maintain the habit.