Second-degree Relatives Of Probands Research Articles

Etiological overlap between obsessive‐compulsive disorder and anorexia nervosa: a longitudinal cohort, multigenerational family and twin study

Obsessive-compulsive disorder (OCD) often co-occurs with anorexia nervosa (AN), a comorbid profile that complicates the clinical management of both conditions. This population-based study aimed to examine patterns of comorbidity, longitudinal risks, shared familial risks and shared genetic factors between OCD and AN at the population level. Participants were individuals with a diagnosis of OCD (N=19,814) or AN (N=8,462) in the Swedish National Patient Register between January 1992 and December 2009; their first-, second- and third-degree relatives; and population-matched (1:10 ratio) unaffected comparison individuals and their relatives. Female twins from the population-based Swedish Twin Register (N=8,550) were also included. Females with OCD had a 16-fold increased risk of having a comorbid diagnosis of AN, whereas males with OCD had a 37-fold increased risk. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for a later diagnosis of AN (risk ratio, RR=3.6), whereas individuals first diagnosed with AN had an even greater risk for a later diagnosis of OCD (RR=9.6). These longitudinal risks were about twice as high for males than for females. First- and second-degree relatives of probands with OCD had an increased risk for AN, and the magnitude of this risk tended to increase with the degree of genetic relatedness. Bivariate twin models revealed a moderate but significant degree of genetic overlap between self-reported OCD and AN diagnoses (ra =0.52, 95% CI: 0.26-0.81), but most of the genetic variance was disorder-specific. The moderately high genetic correlation supports the idea that this frequently observed comorbid pattern is at least in part due to shared genetic factors, though disorder-specific factors are more important. These results have implications for current gene-searching efforts and for clinical practice.

Family patterns of psychopathology in psychiatric disorders

ObjectiveFamilial loading and crucial outcomes of family history of psychopathology in psychiatric disorders have long been recognized. There has been ample literature providing convincing evidence for the importance of family psychopathology in development of emotional disturbances in children as well as worse outcomes in the course of psychiatric disorders. More often, maternal psychopathology seems to have been an issue of interest rather than paternal psychopathology while effects of second-degree familiality have received almost no attention. In this study, we addressed the relations between affected first- and second-degree relatives of probands and categories of psychiatric disorders. MethodSubjects were 350 hospitalized psychiatric inpatients, consecutively admitted to psychiatry clinics in Van, Turkey. Mean age was 34.16 (SD±12) and 51.4% of the sample consisted of male patients. Assessment of psychopathology in psychiatric probands was conducted based on DSM-IV TR. Familial loading of psychiatric disorders amongst first- and second-degree relatives of patients were initially noted primarily relying on patients' retrospective reports, and confirmed by both phone call and following official health records via the Medical Knowledge System. We analyzed the data using latent class analysis approach. ResultsWe found four patterns of familial psychopathology. Latent homogeneous subsets of patients due to familial characteristics were as paternal kinship psychopathology with schizophrenia, paternal kinship psychopathology with mood disorders, maternal kinship psychopathology and core family psychopathology. ConclusionFamily patterns were critical to exerting variation in psychiatric disorders of probands and affected relatives. Probands with a core family pattern of psychopathology exhibited the most colorful clinical presentations in terms of variation in psychopathology. We observed a specificity of intergenerational transmission of psychiatric disorders when family patterns of psychopathology were taken into consideration, even second-degree relatives of psychiatric probands.

Association Between Two Common Polymorphisms of PPARγ Gene and Metabolic Syndrome Families in a Chinese Population

We investigated the association between the two common polymorphisms, C1431T and Pro12Ala of PPARgamma gene, and metabolic syndrome (MS) in a Chinese population. We included 423 subjects with MS and families without MS. Subjects were divided into three groups: MS probands and first- and second-degree relatives of probands, spouses and controls. Each group was then divided into two subgroups according to genotype (Pro/Pro and Pro/Ala for Pro12Ala, CC and CT + TT for 1431C/T). Anthropometric indices, fasting plasma glucose, lipid profile, Sv1 + Rv5 of electrocardiogram and single nucleotide polymorphisms were detected. Frequencies of C1431T genotypes, but not Pro12Ala, were different among the three groups. MS patients with Pro/Ala genotype had higher fasting blood sugar (FBS) levels and Sv1 + Rv5. Controls with Ala allele had lower total cholesterol levels. In relatives, Ala carriers had higher high-density lipoprotein cholesterol (HDL-c) levels. BMI of the different groups were not significant. MS patients with T allele had higher FBS and Sv1 + Rv5. In relatives of MS subjects, T-allele carriers had lower blood uric acid, creatinine and higher HDL-c levels and Sv1 + Rv5. C1431T, but not Pro12Ala polymorphisms, are associated with MS in a Chinese population. In MS patients, Ala allele and T allele are both associated with higher fasting blood sugar and higher left ventricular voltage. In controls, Ala carriers have lower total cholesterol. In MS relatives, Ala carriers had higher HDL-c levels and T-allele carriers had lower uric acid, creatinine and higher HDL-c levels and left ventricular voltage.

The effect of a single BRCA2 mutation on cancer in Iceland

Objective: To estimate the risk of malignant diseases in families of probands with the same mutation in the BRCA2 gene. Design: A cohort study using record linkage of a breast...

Genotype and phenotype in carriers of germline TP53 mutations

We collected data on a large cohort of families with features of Li-Fraumeni syndrome (LFS). To date we have identified germline TP53 mutations in 28 families: 20 of 25 classic LFS and 8 of 20 Li-Fraumeni−like. In addition we have identified germline mutations in 12 other individuals or families with tumors suggestive of LFS. Most mutations are missense or nonsense, but 7 (18%) are splicing mutations. A survey of the literature showed that this is a considerably higher proportion than has been identified by other groups. The proportion of germline TP53 splicing mutations in LFS families may be markedly under-reported. We have examined the biological consequences of these mutations to determine the functional properties of the mutant p53 and to confirm that they are causative mutations. Previous studies have indicated that five main component tumors are associated with LFS: sarcomas, brain and breast tumors, leukemia and adrenocortical carcinoma. We have analyzed the observed incidence of cancers in first- and second-degree relatives of probands in comparison with that expected, on the basis of United Kingdom national cancer rates. The observed pattern of cancers in germline TP53 carriers was highly significantly different from that expected across all ages. Carcinoma of the breast, brain and spinal cord tumors, bone and soft-tissue sarcomas, adrenocortical carcinoma, Wilms tumor and malignant phyllodes tumors were all strongly associated with a germline TP53 mutation. Common carcinomas (such as lung, colorectal, bladder, prostate, cervix and ovarian) did not occur to excess. Germline TP53 mutations are associated with a subset of specific, mainly rare cancers.

Biochemical discrimination of heterozygotes for cystathionine β-synthase (CβS) deficiency

Direct metabolite analyses would be a useful screen to discriminate CβS heterozygotes from non-carriers. We recently found that homocysteine-related metabolite ratios discriminated obligate heterozygotes for CβS deficiency from a control population. In the current study, samples from 55 first and second-degree relatives of probands with CβS deficiency were analyzed for total plasma homocysteine (tHcy), cysteine (tCys), folate (fol), cobalamin (B12), after fasting for 8 hours, and after 100 mg/kg methionine load (PL). Vitamin & smoking histories were obtained. Molecular genotypes were determined and compared to respective biochemical phenotypes.Metabolite differences, between genotyped carriers (n=26) and non-carriers (n=29) were: folate, [(9.7 +/- 1.5 vs 15.6 +/- 1.9μM, p<0.02), erythrocyte folate (efol) (581 +/- 49 vs 372 +/- 48μM, p=0.004) and tHcy [(fasting) and (PL)], [(13.9 +/- 1.1 versus 10.4 +/-1.0 μM, p=0.01) and (58.8 +/- 2.9 vs 34.5 +/- 1.9μM, p=0.013)]. The ratio of [tHcy / (efol X tCys)] after an oral methionine load, provided 100% discrimination of carriers from noncaniers (102 +/- 14.5 vs 30 +/- 2.3, p=0.0001), in non vitamin-takers. Smoking elevated ratios of carriers and noncaniers (159 +/- 19 vs 40 +/- 5, p=0.0002). Smoking increased the sensitivity and specificity of this ratio, and negated the confounding effects of vitamins. Conclusion: the ratio of [tHcy / (efol X tCys)] can discriminate carriers from noncaniers of CβS deficiency.

Negative symptoms of familial schizophrenia breed true in unstable (vs. stable) cerebral-ventricle pedigrees

A pattern of negative symptoms associated with a high rate of ongoing brain and ventricular instability has been described in a cohort of schizophrenia spectrum probands (patients with schizophrenia, schizoaffective disorder depressed and bipolar, and psychosis NOS) (Garver, D.L., Nair, T.R., Christensen, J.D., Holcomb, J., Ramberg, J., Kingsbury, S., 1999. Differential patterns of premorbid functioning, symptoms and neuroleptic response in stable and unstable ventricular-volume schizophrenia. Neuropsychopharmacology 20, in press). The present study contrasts the prevalence of negative symptoms in first- and second-degree relatives of probands with unstable ventricle volume (UnsVV) and stable ventricle volume (SVV). One hundred and sixteen first- and second-degree relatives of 10 probands were interviewed using the SANS, the ‘Characterization of Course: “Pattern of Symptoms” ’ [from Comprehensive Assessment of Symptoms and History (CASH)], SCID and SCID-II by interviewers blind to the status of the proband. Thirty-five of the 116 family members met DSM-IV criteria for schizophrenia, SA depressed, ‘Cluster A’ of the SCID-II (paranoid, schizotypal, schizoid personality disorder), psychosis NOS, or psychotic affective disorder. These 35 family members were defined as falling within a ‘schizophrenia spectrum’ as described by Farmer, A.E., McGuffin, P., Gottesman, I.I., 1987. Arch. Gen. Psychiatry 44, 634–641, but with the addition of DSM-IV affective psychosis. On that basis, the 35 members were considered ‘affected family members’ (AFMs). The remaining 81 family members were considered unaffected. The ‘predominant symptoms of illness‘ (during the past 2–3 years) for 25 of the 35 AFMs could be characterized according to the ‘Patterns of Symptoms‘ derived from the CASH. Twenty-five of the 35 AFMs were found to maintain a predominant symptom pattern during the course of illness, which could be characterized according to the ‘Pattern of Symptoms‘ as ‘predominantly positive‘ or ‘predominantly negative‘. Three of the probands had UnsVV; seven had SVV. Of the 35 AFMs, 11 were related to the UnsVV probands, and 24 were relatives of the SVV probands. The nine rated AFMs of the UnsVV probands showed a trend toward higher SANS scores (7.3±5.1) (mean±s.d.) than the 20 rated AFMs of SVV probands (4.3±5.1) ( p=0.08) at the time of the interview. Eighty-three per cent (eight of 10) of rated affected pedigree members of the pedigrees delineated by probands with UnsVV probands had a predominantly negative symptom course of illness, and 96% (23 of 24) of rated affected pedigree members of the pedigrees with SVV probands had a predominantly positive symptom course of illness during the preceding 2–3 years ( p=0.002). None of the 12 rated affected pedigree members within pedigrees having UnsVV probands were married at the time of the interview; 45% (14 of 31) of affected pedigree members having SVV probands were married ( p=0.004). A psychiatric disorder, characterized by unstable cerebral ventricles and predominant negative symptoms (including avoidance/failure of marital relationships) appears symptomatically to breed true in pedigrees containing schizophrenia-like illnesses.

Occurrence of epilepsies in family members of Indian probands with different epileptic syndromes.

Large numbers of families with many members having seizures have been used to understand the role of hereditary factors in the pathogenesis of human epileptic syndromes. We aimed to establish a genetic database to form a hypothesis on the possible genetic contributions in different epileptic syndromes. The occurrence and patterns of different epilepsies and epileptic syndromes in 1,219 Indian probands and their relatives were studied. The concordance of epilepsies between probands and relatives was also analyzed. Of probands, 231 (19% of 1219) had first- or second-degree relatives affected with seizures. Incidence of family history in probands with generalized epilepsies (GES) and syndrome of single, small, enhancing lesions (SSEL) was comparable and significantly higher than that in probands with localization-related epilepsies (LRES). The ratio of affected first- to second-degree relatives was close to 4:1. Generalized epilepsies were the commonest type of epileptic syndromes seen among all relatives. The proportion of sibs and second-degree relatives with epileptic syndromes similar to probands was significantly greater in the GES group as compared with the concordant relatives of probands with LRES and SSEL. A significant percentage of first- and second-degree relatives of probands with all types of epileptic syndromes have seizures. The risk of relatives being affected varied as a function of the relation with the proband. Concordance of epileptic syndromes between probands and relatives was related to the epileptic syndromes in probands. The syndrome of SSEL is probably a benign epileptic syndrome seen in Indians genetically predisposed to seizures. Hereditary factors may play an almost equal role in the predisposition of relatives to epilepsy in families of probands with different epileptic syndromes.

Prevention of insulin-dependent diabetes mellitus: an overview of three trials.

Genetic, immune, and metabolic testing can reveal a person's risk of developing insulin-dependent diabetes mellitus (IDDM), and three large clinical trials are planned or underway to see if interventions can prevent IDDM in persons at risk. Researchers in diabetes prevention trials are screening first- and second-degree relatives of probands with IDDM for islet-cell antibodies. In the Cow's Milk Avoidance Trial, infant siblings of probands with IDDM will be randomized to receive either a baby formula containing a non-antigenic protein hydrolyzate or a standard cow's milk-based formula. The Diabetes Prevention Trial-Type I is randomly assigning subjects at high risk (more than a 50% probability of developing IDDM) to either receive insulin injections or undergo observation alone; subjects at intermediate risk (25% to 50%) will receive either oral insulin or placebo. In the European Nicotinamide Diabetes Intervention Trial, subjects receive either nicotinamide or placebo. If any of these trials show that IDDM can be prevented, then large-scale screening of children for IDDM risk factors may prove beneficial.

Lack of heritability in ovarian germ cell malignancies

OBJECTIVE: Our purpose was to determine whether relatives of patients with ovarian germ cell malignancies not associated with sex chromosome abnormalities are at increased risk for similar tumors. STUDY DESIGN: We reviewed pedigrees of 78 presumptive 46,XX patients (ages ranging from newborn to 20 years) with malignant ovarian germ cell tumors, excluding cases of dysgerminoma and gonadoblastoma. A three-generation family history of each proband was reviewed specifically to identify cancer in any family member. RESULTS: Seventy-eight mothers, 87 sisters, 135 aunts, and 156 grandmothers were surveyed. None had a malignant ovarian germ cell neoplasm or other malignant ovarian neoplasm. CONCLUSION: First- and second-degree relatives of probands with ovarian germ cell malignancies do not have an increased risk for similar tumors. These findings were not predicted because of the well-recognized association of hereditary tumors and early age of onset. (AM J Obstet Gynecol 1994;170:1803-8.)

Endometrial adenocarcinoma: Genetic analysis suggesting heritable site-specific uterine cancer

Genetic factors are clearly integral to the etiology of neoplasia. A cancer family syndrome (Lynch syndrome II) consisting of uterine, colon, and ovarian cancer is recognized, but the heritability of isolated endometrial adenocarcinoma has not otherwise been thoroughly investigated. We have performed pedigree studies in index cases with endometrial adenocarcinoma, using spouses as controls. Preliminary results from 64 probands showed four families in which endometrial adenocarcinoma was diagnosed in at least one first-degree relative of the proband (mother, daughter, sister); none showed relatives with colon or ovarian cancer. In none of the 34 control pedigrees did either a mother or sister have endometrial adenocarcinoma. In four other families, multiple first- and second-degree relatives of probands had adenocarcinoma of the uterus, colon, or ovary, presumably representing a cancer family syndrome (Lynch syndrome II). Conclusion: Our preliminary data not only show familial and probably heritable tendencies for endometrial adenocarcinoma, but further suggest that there are at least two distinct forms: (1) the previously described Lynch syndrome II (cancer family syndrome), and (2) a heretofore unemphasized entity characterized by a tendency to endometrial adenocarcinoma alone.