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PubMed2005

Saccadic eye movement task identifies cognitive deficits in children with schizophrenia, but not in unaffected child relatives.

BACKGROUND: The delayed oculomotor response (DOR) task requires response inhibition followed by movement of gaze towards a known spatial location without a current stimulus. Abnormalities in response inhibition and in the spatial accuracy of the eye movement are found in individuals with schizophrenia and in many of their relatives, supporting the use of these saccadic abnormalities as endophenotypes in genetic studies. It is unknown whether school-age children, either with psychosis or as relatives of a schizophrenic proband, can be included. METHOD: One hundred eighty-seven children, ages 5.8-16.0 years - 45 children with childhood-onset schizophrenia, 64 children with a first-degree relative with schizophrenia, and 84 typically developing children - completed DOR tasks with 1 and 3 second delays. RESULTS: Children with childhood-onset schizophrenia demonstrated impaired response inhibition and impaired spatial accuracy compared to both relatives and typicals; however, relatives and typicals did not differ from each other. CONCLUSIONS: Children with childhood-onset schizophrenia have saccadic abnormalities similar to those found in adults with schizophrenia, supporting the continuity of executive function deficits in childhood-onset with adolescent and adult-onset schizophrenia. However, saccadic tasks are not sensitive to genetic risk in non-psychotic children and 6-15-year-old children should not be included in genetic studies utilizing this endophenotype.

Adolescent↗

PubMed2006

Visual P300s in long-term abstinent chronic alcoholics.

BACKGROUND: Evidence of reduced P3b amplitudes in chronic alcoholics and individuals at risk for developing alcoholism suggest that the P3b may be an endophenotypic marker for alcoholism. If this is the case, then long-term abstinent alcoholics (LTAAs) should exhibit reduced P3b amplitudes. Thus far, P3b studies on chronic alcoholics have focused primarily on samples with relatively short-term abstinence (less than 15 months). This study examines the amplitude and latency of the P3b and P3a event-related brain electrical components in LTAAs compared with normal controls (NCs) and whether these measures are related to alcohol use and other subject variables. METHODS: Electroencephalographs (EEGs) were recorded on 48 LTAAs (mean abstinence=6.7 years) compared with 48 age-matched and gender-matched NCs during a visual P300 experiment consisting of standard, target, and rare nontarget conditions. This paradigm elicited the P3b (target condition) and the P3a (rare nontarget condition) components. RESULTS: Long-term abstinent alcoholics had reduced P3b amplitudes and increased P3b latencies in comparison with NCs. Long-term abstinent alcoholics also exhibited delayed P3a components, but no P3a amplitude reductions. Alcohol use variables, a family history of alcohol problems, and the duration of alcohol abstinence were not associated with any amplitude or latency variables. CONCLUSIONS: Even after very prolonged abstinence, reduced P3b amplitudes are present in chronic alcoholics and are not associated with any family history or alcohol use variables. These results provide equivocal support for reduced P3b amplitude being an endophenotypic marker for alcoholism, but are also consistent with P3b being affected by a threshold of alcohol abuse, with the effect not resolving over long periods of abstinence.

Adult↗

PubMed2005

The association between attentional and executive controls in the expression of borderline personality disorder features: a preliminary study.

BACKGROUND: Basic neurocognitive functions such as attention and executive cognitive control represent promising endophenotypes that may improve understanding of the development and expression of borderline personality disorders (BPD). We evaluated the association between performance on the Attention Network Task (ANT) and the Wisconsin Card Sorting Test (WCST), two neurocognitive laboratory instruments, and the extent of BPD psychopathology. SAMPLING AND METHODS: We studied 22 BPD-diagnosed individuals who were independently administered these two laboratory assays. Performance on these tests was used as a predictor of the extent of BPD psychopathology. RESULTS: Indexes of the ANT and the WCST were correlated with one another in this sample. Further, the extent of impairment in attention networks, specifically the orienting network, was associated with a greater spectrum of BPD psychopathology, independent of the effects of age and medication status. Finally, ANT and WCST performance were uncorrelated with general psychosocial functioning in this sample, implicating relative specificity to the extent, as contrasted with functional severity, of BPD psychopathology. CONCLUSIONS: Attentional and executive functions are promising endophenotypic markers of BPD psychopathology. The implications of these findings are considered from developmental, experimental, and clinical perspectives.

Adolescent↗

PubMed2005

Evidence for a major gene influence on tumor necrosis factor-alpha expression in tuberculosis: path and segregation analysis.

OBJECTIVE: Tuberculosis (TB) is a growing global public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. METHODS: We conducted a household contact study in a TB-endemic community in Uganda. Antigen-induced tumor necrosis factor-alpha (TNFalpha) expression, a key component of the underlying immune response to TB, was used as an endophenotype for TB. RESULTS: Path analysis, conducted to assess the effect of shared environment, suggested that TNFalpha is heritable (narrow sense heritability = 34-66%); the effect of shared environment is minimal (1-14%), but gene-environment interaction may be involved. Segregation analysis of TNFalpha suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. CONCLUSION: Our data further support TNFalpha as an endophenotype for TB, as it may increase power to detect disease-predisposing loci.

Adolescent↗

PubMed2002

P50 sensory gating in multiplex schizophrenia families from a Pacific island isolate.

OBJECTIVE: Multiplex schizophrenia families from Palau, Micronesia, were assessed with P50 sensory gating to 1) test for replication of the association between this inhibitory neurobiological trait and familial schizophrenia in non-Caucasian subjects and 2) evaluate the ability of the P50 trait to serve as an endophenotype in a genetic linkage study of these families. METHOD: A paired-stimulus auditory event- related potential paradigm was used to examine P50 sensory gating in 85 schizophrenia patients (56 medicated with typical antipsychotics and 29 unmedicated), 83 of their first-degree relatives (46 parents and 37 siblings), and 29 normal comparison subjects. RESULTS: Auditory sensory gating as measured by the P50 ratio was similarly impaired in medicated and unmedicated schizophrenia patients compared to the normal subjects, and medication dose had no significant effect on any P50 variable. This impairment extended to first-degree relatives, who also showed significantly higher P50 ratios than the normal subjects. Abnormal P50 ratios were found in 64.7% of the schizophrenia patients and 51.8% of their first-degree relatives but only 10.3% of the normal subjects. CONCLUSIONS: P50 sensory gating deficits were confirmed in Palauan schizophrenia families. Rates of abnormal P50 sensory gating in relatives versus normal subjects resulted in a risk ratio of 5.0. Impairment was independent of medication effects, indicating that the P50 paradigm measures a stable neurobiological trait unaffected by treatment with typical antipsychotics. These results suggest that this trait can fulfill the major criteria for an endophenotype for genetic liability to schizophrenia in these multiply affected Palauan families.

Adult↗

PubMed2003

Low olfactory bulb volume in first-degree relatives of patients with schizophrenia.

OBJECTIVE: There is a substantial genetic contribution to schizophrenia but no way to readily identify individuals at risk. Biological abnormalities reflecting greater genetic vulnerability may be discovered by examining healthy family members of patients with schizophrenia. There is evidence that olfactory impairments are common in patients. The authors previously reported that patients have abnormal olfactory bulbs, assessed by magnetic resonance imaging (MRI). This study examined olfactory bulbs in patients' relatives to determine whether low bulb volume represents an endophenotypic marker of genetic vulnerability. METHOD: Olfactory psychophysical measures and MRI scans of olfactory bulbs were acquired from 19 healthy first-degree relatives, 20 healthy comparison subjects with similar age and gender distributions, and the 11 patient probands of these relatives. Olfactory bulb volumes were measured by using a reliable region-of-interest procedure. RESULTS: The patients had impaired ability to detect odors and had lower olfactory bulb volumes than the comparison subjects. Although the family members had normal olfactory ability, they exhibited low right bulb volume. The patients had smaller left, but not right, olfactory bulbs than their own healthy relatives. CONCLUSIONS: The findings in family members suggest that structural abnormalities of the olfactory system in schizophrenia may partly reflect preexisting genetic vulnerability to illness. Preliminary analyses suggest that right olfactory bulb volume may serve as an endophenotypic marker of genetic vulnerability, while left bulb volume may reflect overt disease among individuals who share genetic vulnerability. Bulb abnormalities in patients are consistent with reports of cellular abnormalities affecting peripheral olfactory receptor neurons.

Adolescent↗

PubMed1995

Visual fixation and smooth pursuit eye movement abnormalities in patients with schizophrenia and their relatives.

Increasing evidence suggests that smooth pursuit eye movement (SPEM) dysfunction may serve as an endophenotype or genetic marker of schizophrenia. The authors tested SPEM and visual fixation (VF) in 31 patients with schizophrenia, 33 of their first-degree relatives, and 24 patients with major depressive disorder. A high rate of abnormal VF was found in schizophrenic patients and their first-degree relatives, but not in affective disorder patients with or without psychotic features. Rate of VF abnormality distinguished schizophrenic patients from acutely depressed mood disorder patients; SPEM did not. VF and SPEM performance correlated only moderately, suggesting that the pathophysiologies of these two eye movement abnormalities may be partially independent. Implications for identifying a schizophrenia endophenotype are discussed.

Adult↗

PubMed2005

Bivariate genome scans incorporating factor and principal component analyses to identify common genetic components of alcoholism, event-related potential, and electroencephalogram phenotypes.

Genetic components significantly contribute to the susceptibilities of alcoholism and its endophenotypes, such as event-related potential measures and electroencephalogram. An endophenotype is a correlated trait which identifies individuals at risk. Correlated traits could be influenced by shared genes. This study is intended to identify chromosome regions that may harbor common genetic loci contributing to alcoholism, event related potential measures and electroencephalogram. All 143 Collaborative Study on the Genetics of Alcoholism families with 1,614 individuals provided by the Genetic Analysis Workshop 14 were used for the analysis with aldx1 as an alcoholism diagnosis. We carried out factor and principal component analyses on the 12 event-related potentials, then bivariate genome scans on aldx1 and electroencephalogram (ecb21), as well as alcoholism and the principal component scores of the event-related potential measures. A univariate genome scan was also carried out on each trait. Factor and principal component analysis on the event-related potential measures showed that the 4 ttths and 4 ntths belong to one cluster (cluster 1), while the 4 ttdts belonged to another (cluster 2). From each cluster, one principal component was extracted and saved as pc1 (for cluster 1) and pc2 (for cluster 2). The results of genome scans revealed only one chromosome region, chromosome 4 q at about 100 cM, identified by several univariate genome scans including aldx1, ecb21, and pc2, and the evidence of linkage increased significantly in the bivariate genome scans of aldx1 and ecb21 and aldx1 and pc2. Our study suggests that the same quantitative trait locus on the chromosome 4 q region, where ADH3 is located, may influence the risk of alcoholism, variations of electroencephalogram, and the 4 ttdts of the event-related potential measures.

Alcoholism↗

PubMed2005

Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also simulated some marker x marker linkage disequilibrium around some of the genes and also in areas without disease genes. We tried two different methods to simulate the linkage disequilibrium.

Computer Simulation↗

PubMed2006

The IMAGE project: methodological issues for the molecular genetic analysis of ADHD.

The genetic mechanisms involved in attention deficit hyperactivity disorder (ADHD) are being studied with considerable success by several centres worldwide. These studies confirm prior hypotheses about the role of genetic variation within genes involved in the regulation of dopamine, norepinephrine and serotonin neurotransmission in susceptibility to ADHD. Despite the importance of these findings, uncertainties remain due to the very small effects sizes that are observed. We discuss possible reasons for why the true strength of the associations may have been underestimated in research to date, considering the effects of linkage disequilibrium, allelic heterogeneity, population differences and gene by environment interactions. With the identification of genes associated with ADHD, the goal of ADHD genetics is now shifting from gene discovery towards gene functionality--the study of intermediate phenotypes ('endophenotypes'). We discuss methodological issues relating to quantitative genetic data from twin and family studies on candidate endophenotypes and how such data can inform attempts to link molecular genetic data to cognitive, affective and motivational processes in ADHD. The International Multi-centre ADHD Gene (IMAGE) project exemplifies current collaborative research efforts on the genetics of ADHD. This European multi-site project is well placed to take advantage of the resources that are emerging following the sequencing of the human genome and the development of international resources for whole genome association analysis. As a result of IMAGE and other molecular genetic investigations of ADHD, we envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality.

Journal Article↗

PubMed2006

Attention-deficit/hyperactivity disorder: neurophysiology, information processing, arousal and drug development.

In this review, we draw on literature from both animal and human neurophysiological studies to consider the neurochemical mechanisms underlying attention-deficit/ hyperactivity disorder (ADHD). Psychophysiological and neuropsychological research is used to propose possible etiological endophenotypes of ADHD. These are conceptualized as patients with distinct cortical-arousal, information-processing or maturational abnormalities, or a combination thereof, and how the endophenotypes can be used to help drug development and optimize treatment and management. To illustrate, the paper focuses on neuro- and psychophysiological evidence that suggests cholinergic mechanisms may underlie specific information-processing abnormalities that occur in ADHD. The clinical implications for a cholinergic hypothesis of ADHD are considered, along with its possible implications for treatment and pharmacological development.

Acetylcholine↗

PubMed2006

[Experimental models of schizophrenia--a review].

OBJECTIVE: Diagnostic and therapy of somatic diseases like diabetes and hypertension have improved notably with the use of experimental models. For schizophrenia the proposal of a model has made little impact and even scepticism. Nevertheless the most recent studies indicate that "Cognitive Sciences" applied to specific models may help us to find out mechanisms of the disease. This article reviews the models presently under investigation for schizophrenia. RESULTS AND DISCUSSION: The difficulty to model schizophrenia results from the subjectivity of its symptoms, the difficult to reproduce them in animals and the disease complexity. Research on such a complex phenotype can only proceed by separating its components (endophenotypes) from each other and by the respective manipulation of its experimental counterparts, made by specific interventions (e.g. pharmacological, surgical, genetic), in the search of a common mechanism leading to these endophenotypes. For integrating these findings with symptoms a global explanatory theory is required. So far, the disease seems to result from a diffuse neuronal disconnection as a consequence of minor brain abnormalities with a genetic and/or environmental cause. CONCLUSIONS: An integrative approach of the diversity of models presently used may improve our understanding of schizophrenia.

Animals↗

PubMed2001

The primate amygdala mediates acute fear but not the behavioral and physiological components of anxious temperament.

Temperamentally anxious individuals can be identified in childhood and are at risk to develop anxiety and depressive disorders. In addition, these individuals tend to have extreme asymmetric right prefrontal brain activity. Although common and clinically important, little is known about the pathophysiology of anxious temperament. Regardless, indirect evidence from rodent studies and difficult to interpret primate studies is used to support the hypothesis that the amygdala plays a central role. In previous studies using rhesus monkeys, we characterized an anxious temperament endophenotype that is associated with excessive anxiety and fear-related responses and increased electrical activity in right frontal brain regions. To examine the role of the amygdala in mediating this endophenotype and other fearful responses, we prepared monkeys with selective fiber sparing ibotenic acid lesions of the amygdala. Unconditioned trait-like anxiety-fear responses remained intact in monkeys with >95% bilateral amygdala destruction. In addition, the lesions did not affect EEG frontal asymmetry. However, acute unconditioned fear responses, such as those elicited by exposure to a snake and to an unfamiliar threatening conspecific were blunted in monkeys with >70% lesions. These findings demonstrate that the primate amygdala is involved in mediating some acute unconditioned fear responses but challenge the notion that the amygdala is the key structure underlying the dispositional behavioral and physiological characteristics of anxious temperament.

Aggression↗

PubMed2005

[Neuropsychology of attention deficit hyperactivity disorder: relevant theories and empirical studies].

There is a rapidly accumulating body of knowledge related to the neurobiology of Attention Deficit Hyperactivity Disorder (ADHD) stemming from multidisciplinary neuropsychological and neuroimaging studies. This paper is a review of recent knowledge in the context of neuropsychological theory and research in this area. The final section of the article introduces animal models on the subject. It has been emphasized that the controversy regarding the results of neuropsychological studies is semantic rather than substantive. The semantic issue here is believed to be that the term "attention" has to be related to more than one anatomical network among several brain regions. ADHD, which has many cognitive and behavioral dimensions like attention deficit, hyperactivity and impulsivity, has a heterogeneous nature reflecting the neurobiological basis related to parallel information processing models. Based on clinical and neuropsychological data it has been stated that both the orbitofrontal cortex and dorsolateral prefrontal cortex are functionally disturbed in ADHD. However, whether these functional disturbances are related to the prefrontal cortex or other brain regions associated however primarily with this cortex is yet unclear. Dopamine and epinephrine as neurochemical factors and the frontal lobe and basal ganglia as anatomical factors have been found to be especially responsible. Valid endophenotypic features should be determined in order to specify genetic subtypes of neuropsychiatric syndromes. A review of the literature leads us to the conclusion that tests used to assess attentional components like the executive control network and behavioral inhibition could determine valid endophenotypes.

Animals↗

PubMed2006

[Subtypes of specific language impairment in Spanish-speaking children: a cluster analysis of linguistic features].

INTRODUCTION: Specific language impairment (SLI) can be viewed as a continuum with different subtypes depending on the combination of deficits and strengths in each of the components of linguistic behavior. AIM. To analyze the phenomenological profiles in a correlative series of Spanish children in order to facilitate their endophenotypic differentiation and the choice of strategies of intervention. PATIENTS AND METHODS: 86 referred children, aged 4 to 9 years, with a mean non-verbal intelligence quotient of 93 (range 72-114) and accomplishing clinical criteria of SLI. Apart from clinical interview and neurological examination, a protocol of questionnaires and tests was used in all subjects in order to measure their formal (phonological, syntactic, lexical) and functional (semantic and pragmatic) linguistic abilities. A cluster analysis of variables was used in order to investigate SLI subtypes. RESULTS: In the total sample, a 24% of whole series have a pure phonological expressive disorder. 55% of subjects have mixed receptive/expressive disorders; from these, the most pervasive subtype is due to verbal agnosia (11%), but more frequently observed subtypes affect syntax reception and expression combined to difficulties in phonological programming (36%) or in lexical retrieval (8%). Furthermore, 21% of the total sample present with difficulties in pragmatic use of language even if their formal linguistic abilities and non-verbal behavior are normal. CONCLUSIONS: Our empirical approach confirms that the admitted SLI subtypes in international literature applies to Spanish-speaking children for endophenotyping and intervention-planning purposes.

Child↗

PubMed2003

A specific deficit in context processing in the unaffected siblings of patients with schizophrenia.

BACKGROUND: Understanding the biological basis of complex, heritable illnesses such as schizophrenia is facilitated by sensitive and functionally specific measures of intermediate processes. Context processing is a theoretically motivated construct associated with executive function. Impairments in this process have been associated with dysfunction of the prefrontal cortex. In the present study, we evaluated whether a specific deficit in context processing could be associated with the unexpressed genetic liability to schizophrenia. METHODS: Twenty-four patients with schizophrenia, 24 unaffected siblings and 36 control subjects completed a version of the AX task with (1) a condition that required context processing and (2) an expectancy condition in which intact context processing could lead to errors. RESULTS: Patients and unaffected siblings performed relatively worse in the context processing condition, whereas controls performed relatively worse in the expectancy condition. A double dissociation between siblings and controls (F = 9.5, P<.005) constituted strong evidence of a specific deficit in context processing associated with a familial or genetic liability to schizophrenia. Preliminary evidence of high diagnostic efficiency was also noted (specificity, 38%; and sensitivity, 100%). CONCLUSIONS: Context processing deficits have been associated with dorsolateral prefrontal cortex dysfunctions in schizophrenia. Such a dysfunction may occur even when genetic liability to schizophrenia is unexpressed clinically. The present method of demonstrating a double dissociation may be a useful approach to exploring endophenotypes related to specific cognitive and neural processes that can be measured in ways sensitive to subtle group differences.

Adult↗

PubMed2006

Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia.

CONTEXT: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. OBJECTIVES: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. DESIGN: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia. MAIN OUTCOME MEASURES: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping. RESULTS: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. CONCLUSIONS: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.

Adult↗

PubMed2000

Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia.

Many investigators have proposed that biological endophenotypes might facilitate the genetic analysis of schizophrenia. A deficit in the inhibition of the P50 evoked response to repeated auditory stimuli has been characterized as a neurobiological deficit in schizophrenia. This deficit is linked to a candidate gene locus, the locus of the alpha7-nicotinic cholinergic receptor subunit gene on chromosome 15q14. Supportive evidence has been found by other investigators, including: 1) linkage of schizophrenia to the same locus; 2) linkage of bipolar disorder to the locus; and 3) replication of the existence of this neurobiological deficit and its relation to broader neuropsychological deficits in schizophrenia. It is certain that there are many genetic factors in schizophrenia and bipolar disorder; what is needed is a complete and precise description of the contribution of each individual factor to the pathophysiology of these illnesses.

Chromosomes, Human, Pair 15↗