A family-genetic study of girls with DSM-III attention deficit disorder

OBJECTIVE: The authors evaluated family-genetic risk factors in girls with attention deficit disorder and compared these results to findings in the authors' previous study of boys with attention deficit disorder. METHOD: Twenty-one girls with attention deficit disorder and 20 normal comparison girls were consecutively ascertained from a pool of existing and new referrals from a pediatric psychopharmacology unit and a medical pediatric unit of the same urban hospital. First-degree relatives of the attention deficit disordered girls (N = 69) and of the normal girls (N = 71) were also assessed. Both groups of girls and their relatives were evaluated on the basis of structured diagnostic interviews conducted by raters who were blind to the clinical status of the probands. RESULTS: The relatives of the girls with attention deficit disorder had higher risks for attention deficit disorder, antisocial disorders, major depression, and anxiety disorders. The higher risk for attention deficit disorder could not be accounted for by gender or generation of relative, age of proband, social class, or family intactness. These findings are highly consistent with the findings in the authors' previous study of boys with attention deficit disorder, which was conducted with identical methods. CONCLUSIONS: This study provides further support for the validity of the diagnosis of attention deficit disorder in girls and suggests that the genders share a common biological substrate.     

Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples.

We examined 140 probands with attention deficit hyperactivity disorder, 120 normal controls, and their 822 first-degree relatives using "blind" raters and structured diagnostic interviews. Compared with controls, probands with attention deficit hyperactivity disorder were more likely to have conduct, mood, and anxiety disorders. Compared with relatives of controls, relatives of probands with attention deficit hyperactivity disorder had a higher risk for attention deficit hyperactivity disorder, antisocial disorders, major depressive disorder, substance dependence, and anxiety disorders. Patterns of comorbidity indicate that attention deficit hyperactivity disorder and major depressive disorders may share common familial vulnerabilities, that attention deficit hyperactivity disorder plus conduct disorder may be a distinct subtype, and that attention deficit hyperactivity disorder and anxiety disorders are transmitted independently in families. These results extend previous findings indicating family-genetic influences in attention deficit hyperactivity disorder by using both pediatrically and psychiatrically referred proband samples. The distributions of comorbid illnesses in families provide further validation for subgrouping probands with attention deficit hyperactivity disorder by comorbidity.     

Comorbidity in the interpretation of dexamethasone suppression test results in children: a review and report

The dexamethasone suppression test (DST) was administered as part of the initial clinical assessment to 83 children and adolescents who were consecutively referred for outpatient evaluation. All diagnoses were made clinically by a child psychiatrist according to DSM-III criteria. A weight-corrected dose of dexamethasone of 17 micrograms/kg was used. DSM-III diagnoses were made independent of DST results. Patients were stratified into four main diagnostic groups: major depressive disorder (MDD) (N = 27); attention deficit disorder with hyperactivity (ADDH) (N = 22); major depressive disorder plus attention deficit disorder with hyperactivity (MDD + ADDH) (N = 29); and psychiatric controls (PC) (N = 5). Rates of dexamethasone nonsuppression were found to be similarly elevated in children with MDD (29.6%), ADDH (22.7%), and MDD + ADDH (37.9%). All 5 psychiatric control patients had a normal postdexamethasone suppression (0%). A similar pattern of results emerged in a reexamination of the literature on available studies of DST in juveniles which revealed that children with major affective disorders, attention deficit disorder (ADDH), and anxiety disorders had comparable DST results that were significantly higher than the 5.6% rate found in normal controls. These findings provide further support for similarities in DST results between ADDH and MDD in outpatients. Although these results suggest a lack of specificity of the DST as a laboratory aid for the diagnosis of juvenile affective disorders, they are also consistent with findings indicating that the DST may be an index of clinical severity and other findings suggesting a possible association between ADDH and MDD. Despite its limitations, the DST may provide potentially useful clinical and research information regarding the pathophysiology of psychiatric disorders and in alerting clinicians to the presence of serious psychiatric disorders. The findings also stress the relevance of assessing comorbidity in interpreting DST results.     

Evidence of familial association between attention deficit disorder and major affective disorders

With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD + AFF) and those without AFF (ADD), familial risk analyses revealed the following: (1) the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls; (2) the age-corrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD + AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%); (3) the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD + AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%); (4) ADD and AFFs did not cosegregate within families; and (5) there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities.     

Familial association between attention deficit disorder and anxiety disorders

BACKGROUND AND METHOD: This study tested hypotheses about patterns of familial association between attention deficit disorder (ADD) and anxiety disorders among 356 first-degree relatives of 73 clinically referred children with ADD and 26 normal comparison children. Through structured diagnostic interviews with trained raters, relatives were assessed for adult and childhood psychopathology. After stratifying the sample of ADD probands into those with anxiety disorders and those without, the authors examined patterns of aggregation of ADD and anxiety disorders in the relatives of these probands as well as in the relatives of the normal comparison subjects. RESULTS: Familial risk analyses revealed that 1) familial risk for anxiety disorders was higher among all ADD probands than among the normal subjects; 2) familial risk for ADD was similar in the relatives of the ADD probands and of the probands with ADD and anxiety disorder; 3) the relatives of the ADD probands with and without anxiety disorders were at greater risk for ADD than the relatives of the normal subjects; 4) the risk for anxiety disorders was two times higher in the relatives of the probands who had ADD with anxiety disorder than in those of the ADD probands without anxiety disorders; and 5) there was a tendency for ADD probands' relatives who themselves had ADD to have a higher risk for anxiety disorders than ADD probands' relatives who did not have ADD (cosegregation). CONCLUSIONS: The results were most consistent with the hypotheses indicating that ADD and anxiety disorders segregate independently in families.     

Reliability and validity of the structured interview for personality disorders in adolescents

The Structured Interview for the DSM-III Personality Disorders was administered to 23 currently affectively ill adolescents and their parents. Interviews were videotaped and rerated; interrater agreement was moderate (weighted K = 0.49; unweighted K = 0.59). Moreover, there was evidence of convergent validity for Cluster II traits and disorders (borderline, histrionic, narcissistic), insofar as these diagnoses were associated with higher scores on the novelty-seeking subscale of the Tridimensional Personality Questionnaire as predicted. Cluster II patients tended to have higher rates of attention deficit disorder and bipolar disorder, and higher rates of suicidal gestures among second-degree relatives. Some difficulty was encountered differentiating symptoms of affective illness from those of personality disorder and in deciding when personality traits were impairing enough to call them disorders. Reliability may be improved by: (1) interviewing patients when out of affective episode; and (2) using standardized functional impairment criteria for differentiating personality style from disorder. Additional work is advocated to learn if personality disorders are precursors, epiphenomena, or the consequences of affective disorder.     

A controlled family history study of prepubertal major depressive disorder

First-degree (N = 195) and second-degree (N = 785) adult relatives of prepubertal children with major depression (N = 48), children with nonaffective psychiatric disorders (N = 20), and normal children (N = 27) were assessed by the Family History-Research Diagnostic Criteria method (FH-RDC), except for the adult informant (usually the mother), who was directly interviewed. Compared with normal controls, prepubertal children with major depressive disorder (MDD) had significantly higher familial rates of psychiatric disorders in both first- and second-degree relatives, especially MDD, alcoholism, and "other" (mostly anxiety) diagnoses. Relatives of children in the nonaffective psychiatric control (PC) group had low rates of alcoholism, high rates of other (anxiety) disorder diagnoses, and intermediate rates of MDD (accounted for by those children with separation anxiety). This suggests that prepubertal onset of major depression may be especially likely in families with a high aggregation of affective disorders when these families also have a high prevalence of alcoholism, and that a proportion of children without affective disorder but with separation anxiety disorder in this study were at high risk for the development of affective illness later in life. These results support the validity of prepubertal-onset depressive illness as a diagnostic category, and are consistent with high familial rates of MDD and other psychiatric disorders found in family studies of adolescent and early-onset adult probands with major affective disorders, and with studies of the offspring of parents with major affective disorders. Within the child MDD group substantial heterogeneity was found. Low familial rates of MDD were associated with suicidality and comorbid conduct disorder in the child probands. The highest familial rates of MDD, approximately threefold those in the normal controls, and all the bipolar relatives, were found in the families of prepubertal probands with MDD who never had a concrete suicidal plan or act and who were without comorbid conduct disorder. A useful nosological continuum in which to classify prepubertal MDD may be to place at one end those patients with comorbid conduct disorder and at the other end those patients with manifestations related to bipolarity, including hypomania, mania, and psychotic subtype.     

Affective illness in family members and matched controls

As part of the US National Institute of Mental Health Collaborative Program on the Psychobiology of Depression study, a subset of 460 randomly chosen relatives of affectively ill probands were compared to a control group matched by the acquaintanceship method. The rate of major affective disorder in relatives was found to be 36%; the rate among controls was 28%. Relatives were also found to have significantly higher rates of bipolar II disorder, any Research Diagnostic Criteria (RDC) affective disorder and any RDC mental disorder. All of these rates were found to be significantly higher when female relatives were compared with their acquaintances, but only the rate of any RDC mental disorder was higher when this comparison was made in men. The acquaintanceship method enabled the selection of a control group that closely resembled the relatives, probably to the extent of “overmatching”. When the match was evaluated to determine whether relatives tended to select comparably ill (or well) acquaintances, this was found to be the case only for alcoholic and never mentally ill relatives.     

Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder

Using family study methodology and assessments made by blind raters, this study evaluated family-genetic and psychosocial risk factors for DSM-III attention deficit disorder (ADD) among the 457 first-degree relatives of clinically referred children and adolescents with ADD (N = 73), compared with psychiatric (N = 26) and normal controls (N = 26). Relatives of ADD probands had a higher morbidity risk for ADD (25.1% versus 5.3% versus 4.6%, ps less than 0.00001), antisocial disorders (25.3% versus 6.9% versus 4.2%, ps less than 0.00001), and mood disorders (27.1% versus 13.9%, p = 0.038 and 27.1% versus 3.6%, p = 0.00001) than did relatives of psychiatric and normal controls. The increased risk for ADD could not be accounted for by gender or generation of relative, the age of proband, social class, or the intactness of the family. These results confirm and extend previous findings indicating important family-genetic risk factors in ADD.     

White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders

The current study sought to determine the prevalence, severity, and location of white matter signal hyperintensities (WMH) on brain magnetic resonance imaging assessments of children and adolescents with psychiatric disorders. Seventy-one percent (N = 934) of children admitted to the McLean Hospital Child and Adolescent inpatient treatment unit were evaluated with the Diagnostic Interview Schedule for Children (DISC) within 7 days of admission during the period 1988 to 1993 (total, 1,308 admissions). Four hundred eight of these subjects (43.7%) were referred for brain magnetic resonance imaging (MRI) scans and became our study subjects (mean age, 12.4 years [SD = 2.7]; male/female, 230/178). Study subjects were grouped according to a hierarchical diagnostic system as follows: schizophrenia (n = 42), bipolar disorder (n = 56), unipolar depression (n = 94), conduct disorder/attention deficit disorder (n = 103), and other neurotic disorders (n = 30). Subjects without any level 2 diagnosis on DISC (n = 83) constituted the comparison group. Bipolar disorder, unipolar depression, and conduct disorder/attention deficit disorder groups were significantly more likely to have severe levels of WMH than the comparison group (prevalence rates: 17.9%, 13.8%, 13.6% v 1.2%). In addition, the bipolar disorder group was significantly more likely to have severe levels of WMH than the schizophrenia group (prevalence rates: 17.9% v 2.4%). The frontal lobes were the predominant locations of WMH in the bipolar disorder and unipolar depression groups (76.9% and 60.0%, respectively) and also the most frequent location for the conduct disorder/attention deficit disorder group (35.7%). The current study reports an increased prevalence and severity of WMH in children with bipolar disorder, unipolar depression, and conduct disorder/attention deficit disorder relative to the comparison group and in children with bipolar disorder compared to those with schizophrenia. The development of brain WMH, especially in the frontal lobes, may play a role in the pathophysiology of affective disorders in children and adolescents.     

First episode of depression in children at low and high familial risk for depression

OBJECTIVE: To examine the development of first-onset major depressive disorder (MDD) in children at high and low familial risk for depression in a prospective study. METHOD: High-risk children (n = 76) who were free of any lifetime affective disorder and had at least one first-degree and one second-degree relative with a lifetime history of childhood-onset, recurrent, bipolar, or psychotic depression were included. Low-risk children (n = 63) were included if they were free of any lifetime psychiatric disorder and had no first-degree relatives and fewer than 20% of their second-degree relatives with a lifetime affective disorder. Children and their parents were assessed in a prospective design using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version (K-SADS-E). The average interval between follow-up interviews was 18 months, and the average follow-up period was 6 years. RESULTS: High-risk children had approximately a threefold increased risk of developing first-onset MDD compared with low-risk children (odds ratio = 3.21). The average age of new-onset MDD was 14.0 +/- 2.9 years (range 9.5-19.5 years). Above and beyond the familial loading for MDD, mother's lifetime anxiety disorder (odds ratio = 2.84) and lifetime behavioral disorder (odds ratio = 3.25) in the child significantly added to the risk of developing a first-onset MDD. CONCLUSIONS: Having high familial loading for affective disorders, a mother with and anxiety disorder, and a behavioral disorder in the child all significantly contributed to the risk of developing depression.     

Depressed children of depressed parents

Fifty children whose parents had a diagnosis of affective disorder were given a structured diagnostic interview by a child psychiatrist. The parents were also interviewed about their children. Fourteen per cent of the children were found to be depressed. Compared to the remaining children, the depressed children endorsed significantly more symptoms of attention deficit disorder, oppositional disorder, mania, overanxious disorder, phobia, and bulimia in the interview. The parent's interview disclosed that the depressed children were abused significantly more than the non-depressed group.     

Relationship between panic disorder and agoraphobia. A family study

A family study of patients with agoraphobia (n = 40), panic disorder (n = 40), and nonanxious controls (n = 20) showed that the morbidity risk for panic disorder was increased among the relatives of agoraphobics (8.3%) and the relatives of patients with panic disorder (17.3%). The morbidity risk for agoraphobia was also increased among the relatives of agoraphobics (11.6%) but not the relatives of panic disorder patients (1.9%). Male relatives of agoraphobics were shown to be at higher risk for alcohol disorders (30.8%). No greater risk for primary affective disorders was found among the relatives of agoraphobic or panic disorder patients or among the relatives of probands with secondary depression compared with relatives of probands without secondary depression. Probands and relatives with agoraphobia reported an earlier onset of illness, more persistent and disabling symptoms, more frequent complications, and a less favorable outcome than probands and relatives with panic disorder. The findings suggest that agoraphobia is a more severe variant of panic disorder. They also lend support to the separation between anxiety disorders and affective disorders.     

Premorbid IQ in patients with functional psychosis and their first-degree relatives

Numerous studies have found deficits in premorbid IQ in schizophrenic patients, but it is not clear whether this deficit is shared by (a) patients with other functional psychoses, and (b) relatives of these patients. Ninety-one schizophrenic patients, 66 affective psychotic patients (29 schizoaffective and 37 manic or depressed), and 50 normal control subjects were administered the National Adult Reading Test (NART) which provides an estimate of premorbid IQ. The NART was also completed by 85 first-degree relatives of schizophrenic patients and by 65 first-degree relatives of affective psychotic patients. After adjustments were made for sex, social class, ethnicity and years of education, schizophrenic patients had significantly lower premorbid IQ than their relatives, the affective psychotic patients and controls. Manic and depressed patients had significantly lower NART scores than their first-degree relatives, but schizoaffective patients did not, and neither group differed significantly from controls. There was no significant difference in premorbid IQ between patients who had experienced obstetric complications (OC+) and those who had not (OC-). Both OC+ and OC- schizophrenic patients differed significantly from their relatives, but the disparity was greatest between OC+ patients and their relatives. Relatives of OC+ schizophrenic patients had significantly higher IQ than relatives of OC- schizophrenic patients.     

Early onset psychiatric disorder in high risk children and increased familial morbidity

The relationship between child psychopathology and familial morbidity in second degree relatives was examined for children considered at risk on the basis of parental affective illness. Second degree relatives in high-risk families with no child psychopathology were no different from low-risk families in their rates of depression and anxiety. Second degree relatives in high-risk families positive for child psychopathology had significantly higher rates of depression and anxiety than relatives of low-risk children and relatives of high-risk children with no disorder. The implications of these findings are discussed with respect to risk status, prepubertal onset of psychopathology, and familial morbidity for specific psychiatric disorders.     

Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression.

BACKGROUND: Cognitive dysfunction persists in the euthymic phase of bipolar disorder and may provide a marker of underlying neuropathology and disease vulnerability. This study aimed to replicate a deficit in sustained attention in euthymic bipolar patients and investigate sustained attention in first-degree relatives of bipolar probands and in remitted patients with major depressive disorder. METHODS: The rapid visual information processing (RVIP) task was used to measure sustained attention in 15 euthymic patients with bipolar disorder and 15 control subjects in experiment 1 and in 27 first-degree relatives of bipolar probands, 15 remitted patients with major depressive disorder, and 46 control subjects in experiment 2. RESULTS: Sustained attention deficit was confirmed in the euthymic bipolar patients in experiment 1, but the deficit was not statistically significant in remitted major depressed patients or in the relatives of bipolar probands. CONCLUSIONS: A deficit of sustained attention is not present in patients with recurrent major depression tested during remission nor is it discriminable in the first-degree relatives of bipolar probands. Thus, the confirmed abnormality in euthymic bipolar patients may be acquired as a consequence of bipolar illness. However, future studies of relatives will require larger sample sizes to exclude or utilize small genetic effects.     

Suicidal behavior in bipolar manic-depressive patients and their families

There is a high risk of suicidal behavior in patients with primary affective disorder. An extensive investigation in patients with primary affective disorder reported attempted suicide in 26% of bipolar patients and 21% of unipolar patients, the highest rate occurring in female bipolar patients.¹ Woodruff et al.²⁰ found attempted suicide in 14% of unipolar patients as against 32% of bipolar patients with the highest rate in male bipolar patients. Winokur¹⁸ in a study of bipolar manic depressive patients found that 25% of patients had made at least one suicidal attempt and 70% had made threats of suicide at least some time in their lives. Venkabo Rao¹⁶ reported that suicidal ideas occurred in 75% of patients with recurrent affective disorder.Family studies have also reported a high incidence of suicide in the relatives of patients with affective disorder.⁸Mendlewicz et al.⁷ studying a matched group of bipolar probands with and without a family history of manic depressive illness, found high rates of suicide in first and second degree relatives but there was no significant difference in relation to sex or family history. The diagnosis of the relative that suicided was not stated. A study of relatives of patients with primary affective disorder¹⁰ reported that 79% of the suicides in first degree relatives were associated with a diagnosis of probable affective disorder and 10% by a diagnosis of probable alcoholism in the relative. Fathers in index cases were more likely to have committed suicide than mothers. A family history of suicide is considered a major risk factor in assessment of potentially suicidal patients,¹³ however, the relationship between attempted suicide in patients and suicide or attempted suicide in relatives has received little attention and the nature and predictability of this association is uncertain.The following report concerns an analysis of suicidal behavior in a population of bipolar manic-depressive patients and the relationship of this attempt to suicide or attempted suicide in their first and second degree relatives.     

Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder.

OBJECTIVE: Panic attacks are a common complication of affective disorder, although the etiologic relationship of panic and affective symptoms has not been determined. Evidence from a family study suggests that panic attacks and panic disorder may be related genetically to bipolar disorder. This study used diagnostic data from the NIMH Bipolar Disorder Genetics Initiative to assess in a separate, larger family set the familiality of panic combined with bipolar disorder. METHOD: First-degree relatives (N=966) of probands with bipolar I disorder (N=192) and schizoaffective disorder, bipolar type, (N=11) were included in the study. All subjects were interviewed directly and were assigned best-estimate diagnoses for major affective and other psychiatric disorders. The risk of a family member being diagnosed with panic disorder if the proband with bipolar disorder had panic attacks or panic disorder was calculated with logistic regression analysis with generalized estimating equations that controlled for sex and affective disorder subdiagnosis. RESULTS: More than 90% of the probands and first-degree relatives with panic disorder also had an affective disorder diagnosis. Panic disorder was present in 17% of the relatives with recurrent major affective disorder and in 3% of the relatives without recurrent major affective disorder. Risk of panic disorder in relatives with bipolar disorder was increased significantly if the proband had panic attacks or panic disorder. CONCLUSIONS: Risk for panic disorder with familial bipolar disorder appears to be inherited. Inherited risk for panic disorder with bipolar disorder may indicate a shared genetic etiology for both disorders in some families. The patterns of bipolar disorder and panic disorder comorbidity observed in families imply a complex genetic etiology, which may be elucidated by using endophenotypes.     

Affective disorders in the first-degree relatives of bipolar probands: results from the South Island Bipolar Study

The current study was performed to document observed rates of affective disorders in the first degree relatives of probands with bipolar I or II disorder; to determine whether bipolar II probands have an excess of bipolar II relatives; and to determine whether bipolar probands with a history of one or more suicide attempts have more relatives who have also made suicide attempts. Bipolar probands with positive family histories of affective disorder were recruited from a variety of sources for a study on the molecular genetics of bipolar disorder. Probands and relatives were interviewed with the Diagnostic Interview for Genetic Studies (DIGS) and blood was obtained for DNA extraction and genetic analyses. Among 423 first-degree adult relatives of 153 bipolar probands, 7% (29) had bipolar I disorder, 7% had bipolar II disorder, and 7% had bipolar not otherwise specified (NOS) disorder, making 21% of relatives with any bipolar disorder. A further 42% of relatives had a depressive disorder and only 38% had no affective disorder. A suicide attempt by a proband was not associated with any increase in suicide attempts by relatives. We conclude that while unipolar depressive disorders are the most common affective disorders in the first-degree relatives of bipolar probands, extension of the bipolar phenotype to include bipolar spectrum disorders results in 21% of relatives having any bipolar disorder.     

精神分裂症和情感障碍混合家系的遗传调查

目的 探讨精神分裂症和情感障碍混合家系的遗传效应。方法 采用严格的纳入标准,应用家族史法对55例混合家系的各级亲属2134人进行详细的调查记录。分三组进行分析。结果 (1)精神分裂症为先证者组,各级亲属精神分裂症的患病率为1.1％,与1993年全国七地区调查精神分裂症的群体患病率0.655％比较,P>0.05,统计学上无显著差异,一级亲属患病率为4.79％,各群体比较,P<0.05。各级亲属情感障碍的患病率为3.78％,与1992年全国七地区调查情感障碍的群体患病0.083％比较,P<0.05,统计学上有显著差异,一级亲属患病率为17.96％。(2)情感障碍为先证者组,各级亲属情感障碍患者率为1.234％,与群体比较,P<0.05,一级亲属患病为4.76％。各级亲属精神分裂症的患病率为3.67％,与群体比较,P<0.05,一级亲属患病率为12.24％。(3)混合组,各级亲属精神分裂症的患病率为2.27％,与群体比较,P<0.05,一级亲属患病率为9.44％。结论 混合家系中,血缘关系越近,亲属中精神分裂症和情感障碍的患病率越高;精神分裂症和情感障碍在遗传传递上可能具有交叉性。