<!-- image -->

Research Article                                                                                                                                        Open Access

## Familiality of Quantitative Autism Traits

Katja Jussila 1,2* , Kristen Lyall 3,4 , Sanna Kuusikko-Gauffin 1,2 , Marja-Leena Mattila 1,2 , Rachel Pollock-Wurman 5 , Tuula Hurtig 1,2,6 , Leena Joskitt 1,2 , Risto Bloigu 1 , Hanna Ebeling 1,2 , Irma Moilanen 1,2 , David Pauls 5,7

1 PEDEGO Research Unit, Child Psychiatry, University of Oulu, Finland 2 Clinic of Child Psychiatry,   Oulu University Hospital, Finland 3 Harvard School of Public Health, Department of Nutrition, USA 4 University of California, Davis, Department of Public Health Sciences, USA 5 Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, USA 6 Neuroscience Research Unit, Psychiatry, University of Oulu, Finland 7 Psychiatric & Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, USA

*Corresponding author: Katja.Jussila@oulu.fi; Katja.Jussila@gmail.com

## Abstract

Background: Autistic traits exist along a continuum that extends into social functioning in the general population, and they aggregate  in  the  family  members  of  children  with  autism  spectrum  disorder  (ASD).  Quantitative  measures  are  therefore essential  when investigating the patterns of familiality of  these traits. Prior  studies  have suggested differential inheritance patterns of autistic traits that depend on the cognitive level of the child with ASD as well as the family type.

Objective: Our goal was to examine the family patterns of quantitative autism traits (QAT) in a group of simplex autism families of high-functioning children with ASD.

Method: We used the Social Responsiveness Scale (SRS) to evaluate QAT in 47 ASD families and 46 control families. SRS assessments (parental/spousal evaluations) were collected for the children with ASD, their siblings, and their parents as well as for the control children and their parents.

Results The SRS was able to distinguish individuals with ASD from the control children and from their unaffected siblings. Significant  group differences were also found when comparing the fathers of ASD families to control fathers and when comparing the brothers of individuals with ASD to control boys, with male members of ASD families having higher SRS scores.  Gender  differences  were  observed  in  the  group  of  siblings  of  children  with  ASD  and  the  group  of  parents  of children with ASD, with males having higher scores than females. In ASD families, a positive trend between child and father QAT  was  found,  whereas  mothers'  scores  were  not  associated  with  child  outcomes.  By  contrast,  in  control  families, mothers' QAT correlated more strongly with child QAT.

Conclusions: Autistic  traits  aggregate  in  the  fathers  and  brothers  of  children  with  ASD  in  simplex  autism  families.  The QAT levels  of  the  family  members  should  be  taken  into  consideration  when  planning  the  rehabilitation  of  the  child  or adolescent with ASD and when designing family interventions.

Keywords: autism spectrum  disorder, autistic traits, quantitative autism traits, broader autism phenotype, Social Responsiveness Scale

## Introduction

Autism  spectrum  disorder  (ASD)  is  a  childhood neurodevelopmental  disorder  that  is defined by impairment  in  social  development  and  communication as well as the presence of marked repetitive behaviors  and  narrow  interests  (1).  There  is  wide variability in the phenotypic manifestation of ASD, but the central feature may be considered a deficit in reciprocal social behavior.

The term reciprocal social behavior refers to the extent to  which  an  individual  can  engage  in  emotionally appropriate, turn-taking social interaction with others. Reciprocal social behavior requires the individual  to  be  cognizant  of  the  emotional  and interpersonal cues of others, to appropriately interpret  and  respond  to  those  cues,  and  to  be capable of emotional  engagement  (2).  There  is evidence that ASD traits are continuously distributed  in  the  general  population,  genetically transmitted  across  generations,  and  aggregated  at subclinical  levels  in  relatives  of  individuals  with autism (2-15). The phenotypic profile of subthreshold  ASD  traits  that  manifest  in  some relatives of autistic individuals has been referred to as the broader autistic phenotype (4); when measured by quantitative  instruments,  these  broader  deficits  in social functioning are called quantitative autism traits  (QAT)  (13).  The  broader  autistic  phenotype has  been  thought  of  as  an  index  of  family  genetic risk for autism (16).

Many family studies have used categorical definitions (i.e., present/absent) of the broader autistic  phenotype  in  the  same  way  that  diagnostic classifications  of  ASD  are  categorical.  However, given  evidence  that  autistic traits exist along  a continuum  that  extends  into  social  functioning  in general population and that these quantitative traits are strongly heritable, quantitative  measures  are essential when investigating patterns of family inheritance. The Social Responsiveness Scale (SRS) is a widely used quantitative questionnaire regarding autistic  traits  that  reliably  measures  QAT  and  that yields a total score to quantify these traits (2).

Prior studies have suggested differential inheritance patterns of autistic traits that depend on both  the  cognitive  level  of  the  child  with  ASD (17) and the family type (i.e., simplex vs. multiplex) (13,14,18).  In  this  study,  our  goal  was  to  evaluate whether  quantified  autistic  traits  aggregate  in  and are correlated among family members in a sample of simplex  families  of  high-functioning,  school-aged children with ASD. We also sought to examine the familiality  of  subclinical  QAT  in  the  families  of control children.

## Methods

Participants

Participants  were  drawn  from  a  clinically  based molecular  genetic  study,  the  details  of  which  have been previously reported (19). The study was conducted  in  2003  in  the  Northern  Ostrobothnia Hospital  District  area  in  the  Providence  of  Oulu, Finland, and approved by the Northern Ostrobothnia  Hospital  District  Ethics  Committee. The target population included all elementary school-aged  children  7  to  16  years  old  with  the following  characteristics:  1)  they  were  outpatients who  had been diagnosed with ASD  at Oulu University  Hospital;  2)  they  had  undergone  fullscale  intelligence  quotient  testing  that  found  them to  be  in  the  normal  range;  and  3)  they  carried  no additional diagnoses of speech or language disorders, hearing impairments, or fragile X syndrome.  The  families  of  60  children  met  the inclusion criteria and were invited to participate.

Invitation  letters  that  included  a  preliminary  fact sheet about the study protocol and objectives were sent to the parents of the children, and a time for a confirmatory  phone  call  was  scheduled  in  each letter. Psychologists (KJ or SKG) called the parents at the designated time to inquire about each family's willingness to participate in the study and to answer any  questions  the  parents  might  have  about  the research. Parents were also asked whether they (or the  school  personnel  familiar  with  their  children) had  concerns  about  their  other  children  having ASD; the siblings  of  identified  children  with  ASD were accepted into the proband group at this point. The  SRS  questionnaire  and  the  Autism  Spectrum Screening  Questionnaire  (ASSQ)  (20,21)  were  sent to  the  parents  of  the  families  that  were  willing  to participate.  Parents  were  asked  to  complete  both questionnaires  for  the  evaluation  of  all  of  their children;  the  SRS  was  also  used  by  each  parent  to evaluate  the  other  parent.  Written  consent  was obtained  from  all  parents  and  from  children  who were more than 12 years old.

Families  were  subsequently  invited  to  the  Oulu University Hospital outpatient clinic, where confirmatory diagnostic assessments were performed. A single day was reserved for each child evaluation. The clinical diagnoses of the outpatients had  previously  been  assigned  on  the  basis  of  the diagnostic criteria  regarding  current  behavior  as defined  by  the International  Statistical  Classification  of Diseases and Related Health Problems, 10th Revision (22). In  this  study,  diagnoses  were  reassigned  with  the use  of  the  Autism  Diagnostic  Interview-Revised (ADI-R)  and  the  Autism  Diagnostic  Observation Schedule (ADOS), and the early development of the children  was  checked  with  the  use  of  their  patient records. The ADI-R interviews of parents and the ADOS observations of children were administered by  a  clinical  psychologist  who  had  been  trained  in the use of these instruments for research purposes (KJ). After these investigations, diagnoses  were redefined in detail on the basis of all available data (i.e., ADI-R and ADOS data as well as information from patient records), in accordance with the Diagnostic  and  Statistical  Manual  of  Mental  Disorders, Fourth Edition criteria (23), and also after taking into account  the  development  that  occurred  during  the first 3 years of each child's life. Consensus diagnoses were established between  the clinical psychologist (KJ) and a pediatrician who  was clinically  experienced  in  the  autism  field  (M-LM). Diagnostic evaluations were also performed for all siblings of outpatients with ASD for whom parents had reported possible concerns about ASD.

Control children were recruited from two mainstream  elementary  schools  in  Oulu,  Finland. One class of students from each of the first through ninth  grades  was  randomly  selected  and  invited  to participate  in  the  study  with  their  families  (210 students).  Families  of  88  students  participated  (82 families in total; six children were siblings from the same  families).  Controls  were  screened  with  the ASSQ, and those exceeding 7 points were excluded (24). We subsequently checked all potential participants' hospital records to ensure that none of the control children were ASD outpatients of Oulu University Hospital. At that time, the Oulu University  Hospital  was  the  only  facility  in  the Northern Ostrobothnia Hospital District area where ASD diagnoses were made.

Individuals who did not meet publisher requirements for the scoring of the SRS (i.e., >10% missing items) were excluded, and only families with satisfactory SRS  data  from  at least  two  family members  (including  the  child  with  ASD  or  the control  child)  were  included  in  analyses.  Multiplex ASD families were also excluded (i.e., families with more than one child with ASD; this was a total of three families). The final study sample consisted of 47 ASD families and 46 control families (of which five included two control children).

## Measures

The  Autism  Diagnostic  Interview-Revised. The  ADI-R (25) is a standardized, investigator-based,  semistructured parental interview that was developed to elicit the full range of information about the criteria necessary to evaluate and diagnose ASD. The ADIR  covers  the  main  symptom  areas  associated  with ASD, including reciprocal social interaction, communication, and restricted and stereotyped behaviors and interests.

The Autism Diagnostic Observation Schedule. The ADOS (26) is a semi-structured assessment of social interaction, communication, and play or imaginative use of materials. It comprises four modules that are based  on  the  verbal  level  of  the  individual  who  is being evaluated.

Both  the  ADI-R  and  the  ADOS  make  use  of diagnostic  algorithms  that  are  based  on  separate thresholds for ASD symptom domains. The domain scores  are  the  sums  of  codings  that  indicate  the severity  of  impairment  on  the  basis  of  symptom frequency and the degree of interference with daily living.

The Social Responsiveness Scale. The SRS (2,27) is a 65item measure of autistic traits, which are rated on a Likert-type scale that ranges from 0 (not true) to 3 (almost  always  true).  These  questions  yield  a  total continuous  score  (raw  score  range,  0  to  195)  that can be interpreted as the  level  of  QAT.  SRS questions  cover  the  dimensions  of  communication and the behavior characteristics of ASD. Subscales that  represent  different  aspects  of  the  capacity  for reciprocal social behavior can also be obtained from the SRS: perception (Social Awareness, 8 items; raw score  range,  0  to  24);  cognition  (Social  Cognition, 12 items; raw score range, 0 to 36); communication (Social Communication, 22 items; raw score range, 0 to 66); motivation (Social Motivation, 11 items; raw score  range,  0  to  33);  and  characteristic  autistic preoccupations  (Restricted  Interests  and  Repetitive Behavior,  12  items;  raw  score  range,  0  to  36)  (2). The  SRS  is  highly  psychometrically  sound,  and  it demonstrates excellent construct validity when compared with the ADI-R. Scores are unrelated to intelligence level or age (9,28).

The Autism Spectrum Screening Questionnaire. The ASSQ (20,21) is a 27-item parent or teacher-report inventory  that  is  designed  to  screen  for  ASD  in children  with  full-scale  intelligence  quotient  ≥50). Of the ASD screening measures, the ASSQ is the only questionnaire that has been validated for Finland  (24).  The  ASSQ  covers  the  main  areas  of ASD  (i.e.,  social  interaction,  communication,  and restricted and repetitive behaviors) as well as motor deficits  and  behaviors  (e.g.,  clumsiness)  and  other associated  symptoms  (e.g.,  motor  and  vocal  tics). Items are rated on a 3-point Likert-type scale (i.e., 0 = normal, 1 = some abnormality, and 2 = definite abnormality), with total scores ranging from 0 to 54 and  higher  scores  indicating  more  severe  levels  of social impairment.

## Statistical Analyses

Analyses  were  performed  with  the  SPSS  statistics package version 17.0. For the replacement of missing data, the expectation-maximization algorithm imputation method was used for cases in which less than 10% of the SRS items were missing. To  correct  for  skewed  data  regarding  the  SRS outcomes  of  the  siblings  and  parents  of  children with ASD, we employed the non-parametric MannWhitney U test to examine group differences in SRS scores.

When investigating the familiality of the QAT, we first looked at the correlations between  family members'  scores;  specifically,  we  examined  partial correlations while controlling for the children's ages. We subsequently conducted a quartile split of child SRS  scores  despite  a  known  decrease  in  group sample  size  to  graphically  compare  child-parent groups on the basis of high and low levels on the SRS. Box plots (Figure 1) were created to show the distributions of parent scores by child quartile.

## Results

Within-Group  Differences  in  Social  Responsiveness  Scale Outcome Measures

Gender  differences  in  SRS  scores  emerged  in  the groups  of  siblings  and  parents  of  children  with ASD.

In the sibling group, brothers of individuals with ASD had higher SRS total scores than the sisters of individuals with ASD (23.9 ± 23.2 vs. 12.2 ± 8.0; p =  .032). Brothers also had significantly higher scores  (as  compared  with  sisters)  on  the  subscales of  Social  Cognition  (4.3  ±  4.9  vs.  2.0  ±  1.3; p = .042) and Social Motivation (5.5 ± 4.3 vs. 2.9 ± 2.7; p = .021). No statistically significant gender differences  were  found  in  the  SRS  scores  of  the groups of children with ASD or the control children (see Table 1).

In  the  group  of  parents  of  children  with  ASD, fathers  had  significantly  higher  SRS  total  scores than did mothers (38.2 ± 29.6 vs. 24.1 ± 21.7, p = .014).  According to the SRS subscales, fathers also had significantly higher scores in the Social Awareness (5.2 ± 4.2 vs. 3.6 ± 3.0; p = .041), Social Communication  (13.0  ±  10.8  vs.  6.0  ±  7.6; p = .001), and Restricted Interests and Repetitive Behavior  subscales  (6.2  ±  6.7  vs.  3.7  ±  4.3; p = .048)  as  compared  with  mothers.  No  significant differences were found when comparing the fathers of  control  children  with  the  mothers  of  control children (see Table 2).

Between-Group  Differences  in  Social  Responsiveness  Scale Outcome Measures: Children

No statistically significant group differences emerged when examining the mean ages of the child groups (ASD probands: n = 47, 39 boys and 8 girls, age 11.3 ± 2.1 years; ASD siblings: n = 43, 23 boys and 20 girls, age 10.9 ± 2.3 years; controls: n = 51, 26 boys and 25 girls, age 11.3 ± 2.5 years). The SRS scores  for  the  ASD  probands  were  significantly higher  as  compared  with  their  siblings  and  with control children when it came to the SRS total score as well as all of the SRS subscale scores (Table 3).

The brothers of children with ASD  scored statistically significantly higher on the Social Motivation  subscale  as  compared  to  control  boys (5.5  ±  4.3  vs.  3.1  ±  2.1; p =  .014)  (Table  1). Although the results were not statistically significant,  brothers  of  individuals  with  ASD  had higher SRS total scores than did control boys (23.9 ±  23.2  vs.  17.1  ±  8.9),  with  a  mean  difference  in SRS  scores  of  6.8  and  an  effect  size  of  1.7  (very large).

The sisters of children with ASD had significantly lower scores on the Social Awareness and Social Cognition subscales as compared with the control girls (2.5 ± 1.7 vs. 3.8 ± 2.1; P = .025, and 2.0 ± 1.3 vs. 3.2 ± 1.8; p = .014, respectively) (see Table 1).

TABLE 1. Social Responsiveness Scale Raw Scores of Siblings of Children With Autism Spectrum Disorder and Control Children by Gender

| Social Responsiveness Scale Scores (Mean ± Standard Deviation)   | Brothers of Children With ASD (n = 23)   | Control Boys (n = 26)   | Sisters of Children With ASD (n = 20)   | Control Girls (n = 25)   |
|------------------------------------------------------------------|------------------------------------------|-------------------------|-----------------------------------------|--------------------------|
| Total Score*                                                     | 23.9 ± 23.2 *                            | 17.1 ± 8.9              | 12.2 ± 8.0 *                            | 18.1 ± 12.1              |
| Social Awareness                                                 | 3.9 ± 3.3                                | 4.9 ± 1.9               | 2.5 ± 1.7 *                             | 3.8 ± 2.1 *              |
| Social Cognition                                                 | 4.3 ± 4.9 *                              | 3.4 ± 2.5               | 2.0 ± 1.3 *                             | 3.2 ± 1.8 *              |
| Social Communication                                             | 7.7 ± 8.5                                | 5.6 ± 3.7               | 4.0 ± 3.3                               | 5.9 ± 5.2                |
| Social Motivation                                                | 5.5 ± 4.3 *                              | 3.1 ± 2.1 *             | 2.9 ± 2.7 *                             | 4.0 ± 3.2                |
| Restricted Interests and Repetitive Behavior                     | 2.5 ± 4.3                                | 1.0 ± 1.2               | 0.9 ± 1.3                               | 1.2 ± 1.7                |

* p < .05 (two-tailed test);

Brothers of Children With ASD > Sisters of Children With ASD for Total Score,

Social Cognition, and Social Motivation; Brothers of Children With ASD > Control Boys for Social Motivation;

Sisters of Children With ASD < Control Girls for Social Awareness and Social Cognition;

ASD, Autism spectrum disorder Between-Group  Differences  in  Social  Responsiveness  Scale Outcome Measures: Adults No  statistically  significant  differences  were  found with regard to the ages of the parent groups (ASD parents:  n  =  85,  age  41.5  ±  6.3  years;  control parents:  n  =  81,  age  41.3  ±  5.2  years).  For  the parent  groups,  the  total  SRS  scores  of  fathers  of children  with  ASD  were  statistically  significantly higher as compared with the total SRS scores of the fathers of control children: SRS total score, 38.2 ± 29.6 versus 19.0 ± 13.4 ( p < .001); Social Awareness,  5.2  ±  4.2  versus  3.5  ±  2.2  ( p =  .019); Social  Cognition,  7.2  ±  6.2  versus  3.2  ±  2.8  ( p < .001), Social Communication, 13.0 ± 10.8 versus 6.5 ± 5.4 ( p < .001); Social Motivation, 6.6 ± 5.3 versus 4.2  ±  3.8  ( p =  .017);  and  Restricted  Interests  and Repetitive Behavior, 6.2 ± 6.7 versus 1.7 ± 1.6 ( p < .001).

Familial  Associations  between  Social  Responsiveness  Scale Scores

When investigating the  familiality  of  the  QAT,  we first  looked  at  the  correlations  between  children's SRS scores  and  those  of  their  parents.  Statistically significant positive correlations were observed between  the  SRS  scores of children and  their parents in all child groups (ASD probands, siblings, and  control  children),  although  these  correlations were moderate. Partial correlation coefficients (controlling for child age) between child and parent SRS scores are presented in Table 4.

Mothers' scores did not differ significantly for any of the SRS outcome measures (Table 2).

Despite  a  known  decrease  in  the  group  sample sizes, to graphically compare child and parent scores on the basis of high and low levels on the SRS, we conducted a  quartile  split  of  children  according  to total  SRS  scores.  We  observed  a  positive  trend  in the families of children with ASD: the father's SRS score increased as the child's quartile increased (see Figure 1). No such trend was evident for mothers' scores or among control children.

TABLE 2. Social Responsiveness Scale Total and Subscale Raw Score Means by Parent Group

| Social Responsiveness Scale Scores           | Fathers of Children With ASD (n = 44) (Mean ± Standard Deviation)   | Control Fathers (n=43) (Mean ± Standard Deviation)   | Fathers of Children With ASD vs. Control Fathers ( p Value)   | Mothers of Children With ASD (n = 41) (Mean Standard Deviation)   | Control Mothers (n = 38) (Mean ± Standard Deviation)   | Mothers of Children With ASD vs. Control Mothers ( p Value)   |   Fathers of Children With ASD vs. Mothers of Children With ASD ( p Value) | Control Fathers vs. Control Mothers ( p Value)   |
|----------------------------------------------|---------------------------------------------------------------------|------------------------------------------------------|---------------------------------------------------------------|-------------------------------------------------------------------|--------------------------------------------------------|---------------------------------------------------------------|----------------------------------------------------------------------------|--------------------------------------------------|
| Total Score                                  | 38.2 ± 29.6                                                         | 19.0 ± 13.4                                          | <.001                                                         | 24.1 ± 21.7                                                       | 21.3 ± 21.7                                            | NS                                                            |                                                                       .014 | NS                                               |
| Social                                       | 5.2 ± 4.2                                                           | 3.5 ± 2.2                                            | .019                                                          | 3.6 ± 3.0                                                         | 4.3 ± 3.0                                              | NS                                                            |                                                                       .041 | NS                                               |
| Social Cognition                             | 7.2 ± 6.2                                                           | 3.2 ± 2.8                                            | .001                                                          | 5.4 ± 5.0                                                         | 3.8 ± 5.0                                              | NS                                                            |                                                                       .152 | NS                                               |
| Social                                       | 13.0 ± 10.8                                                         | 6.5 ± 5.4                                            | <.001                                                         | 6.0 ± 7.6                                                         | 6.3 ± 7.6                                              | NS                                                            |                                                                       .001 | NS                                               |
| Communication Social Motivation              | 6.6 ± 5.3                                                           | 4.2 ± 3.8                                            | .017                                                          | 5.5 ± 4.6                                                         | 4.2 ± 4.6                                              | NS                                                            |                                                                       .281 | NS                                               |
| Restricted Interests and Repetitive Behavior | 6.2 ± 6.7                                                           | 1.7 ± 1.6                                            | <.001                                                         | 3.7 ± 4.3                                                         | 2.7 ± 2.8                                              | NS                                                            |                                                                       .048 | NS                                               |

Results obtained with the Mann-Whitney U test;

ASD, Autism spectrum disorder; NS, not significant

TABLE 3. Social Responsiveness Scale Raw Scores of Child Groups

|                                                                | Child Group (n)        | Child Group (n)                    | Child Group (n)       |
|----------------------------------------------------------------|------------------------|------------------------------------|-----------------------|
| Social Responsiveness Scale Scores (Mean ± Standard Deviation) | Children With ASD (47) | Siblings of Children With ASD (43) | Control Children (51) |
| Total Score                                                    | 92.1 ± 24.0            | 18.4 ± 18.6                        | 17.6 ± 10.5           |
| Social Awareness                                               | 10.8 ± 4.2             | 3.2 ± 2.8                          | 3.9 ± 2.0             |
| Social Cognition                                               | 17.6 ± 6.6             | 3.3 ± 3.8                          | 3.3 ±2.1              |
| Social Communication                                           | 31.2 ± 5.8             | 5.9 ± 6.8                          | 5.8 ± 4.5             |
| Social Motivation                                              | 14.0 ±3.5              | 4.3 ± 3.9                          | 3.5 ± 2.7             |
| Restricted Interests and Repetitive Behavior                   | 18.6 ± 1.1             | 1.7 ± 3.3                          | 1.1± 1.4              |

Results obtained with the Mann-Whitney U test;

All p levels <.0001 for Children With ASD versus Siblings of Children With ASD;

All p levels <.0001 for Children With ASD versus Control Children;

All p levels non-significant for Siblings of Children With ASD versus Control Children; ASD, Autism spectrum disorder

Child quutil fatal

TABLE 4 . Partial Correlation Coefficients Between Child and Parent Social Responsiveness Scale Scores After Controlling for Age

|                          | ASD Proband   | Sibling of Child With ASD   | Control Child   |
|--------------------------|---------------|-----------------------------|-----------------|
| Total Score              |               |                             |                 |
| Father                   | .55**         | .39*                        | .43*            |
| Mother                   | .17           | .42*                        | .54**           |
| Social Awareness         |               |                             |                 |
| Father                   | .59**         | .39*                        | .43*            |
| Mother                   | -.03          | .26                         | .61**           |
| Social Cognition         |               |                             |                 |
| Father                   | .59**         | .44*                        | .35*            |
| Mother                   | .12           | .46*                        | .31*            |
| Social Communication     |               |                             |                 |
| Father                   | .53**         | .33                         | .40*            |
| Mother                   | .23           | .43*                        | .50**           |
| Social Motivation        |               |                             |                 |
| Father                   | .20           | .22                         | .17             |
| Mother                   | .06           | .30                         | .39*            |
| Restricted Interests and |               |                             |                 |
| Repetitive Behavior      |               |                             |                 |
| Father                   | .51**         | .40*                        | .20             |
| Mother                   | .07           | .29                         | .39*            |

* p < .05 (two-tailed test); ** p < .01 (two-tailed test); ASD, Autism spectrum disorder

FIGURE 1 . Distributions of Children With Autism Spectrum Disorder's and Control Children's and Their Parents' Social Responsiveness Scale Total Raw Scores on the Basis of Child Quartiles of Social Responsiveness Scale Total Raw Scores

## ASD Families

## Control Families

1, Lowest child quartile; 4, Highest child quartile; ASD, autism spectrum disorder; SRS, Social Responsiveness Scale

<!-- image -->

## Discussion

Our primary aim was to examine family patterns of the  broader  autistic  phenotype  by  measuring  QAT in  the  first-degree  relatives  of  children  with  ASD with  the  use  of  the  SRS  questionnaire.  We  have previously  found  the  Finnish  SRS  to  be  a  valid measure for differentiating children with ASD from a  normative  peer  sample;  it  demonstrates  strong convergent  validity  with  the  ASSQ,  which  is  an ASD trait  questionnaire  used  in  Finland  in  clinical settings with high-functioning school-aged children (29). The present study demonstrates the aggregation of autistic traits among  the  family members  of  children  with  ASD.  Specifically,  we found  that  the  fathers  and  brothers  (but  not  the mothers or sisters) of children with ASD had higher levels  of  autistic  traits  as  measured  by  the  SRS  as compared with their control counterparts and that, in  ASD  families,  fathers'-but  not  mothers'-trait severity  was  significantly  associated  with  child  trait severity.  By  contrast,  in  the  families  of  typically developing children, mothers' QAT had a stronger association  with  child  SRS scores than  did fathers' QAT.

Our analyses of the familial associations of QAT revealed that, in ASD families, child QAT was more strongly associated with paternal than maternal QAT. Elevated QAT in male but not female family members  of  individuals  with  ASD  has  also  been demonstrated in prior literature. For example, Lyall and  colleagues  (15)  reported  a  significant  risk  in offspring ASD on the basis of elevated SRS scores in  fathers  but  not  mothers.  In  their  prospective longitudinal  infant  sibling  study  of  familial  QAT, Schwichtenberg  and  colleagues  (14)  reported  the highest rates of QAT in the fathers and siblings of ASD  families. Virkud and colleagues (13) also demonstrated the aggregation of subclinical autistic traits  among  the  brothers  and  fathers  of  multiplex ASD families but not among the mothers.

In our study sample, the mothers of  ASD probands did not differ significantly on any of the SRS scales from the mothers of controls; however, the  sisters  of  children  with  ASD  demonstrated certain differences from control girls, with significantly lower scores (indicating higher functioning)  on  the  Social  Awareness  and  Social Cognition subscales. One explanation for this seemingly contradictory finding is that the ability of a  typically  developing  female  sibling  to  adapt  to  a family  system  where  there  is  a  sibling  with  special needs may be enhanced. It is also possible that the low scores of the sisters of children with ASD may reflect  the  way  parents  assess  their  daughters  with no special needs (as compared to their children with ASD).  Virkud  and  colleagues  (13)  found  that  the aggregation of QAT was observed in only the male siblings of children with ASD, even in the multiplex families. These results may support gender differences in both QAT inheritance and diagnostic clinical  practice.  Moreover,  as  suggested  by  other researchers  (30,31),  higher  levels  of  family  QAT may be required for  girls  to  meet  clinical  levels  as measured by these scores. The current study did not have a sufficient sample size to fully explore gender differences  with  high  statistical  power,  but  these issues should be further investigated in future studies.

A recent large family study conducted by Constantino and colleagues (18) that included 1235 families  and  2920  children  demonstrated  that  the sibling  recurrence  of  ASD  varies  as  a  function  of family type (i.e., simplex vs. multiplex).  QAT aggregation  was  found  in  unaffected  children  of multiplex  ASD  families  but  not  in  simplex  ASD families. Consistent with this was that Schwichtenberg  and  colleagues  (14)  found  infant siblings from multiplex families to be at significantly higher risk for ASD  as  compared  with  infant siblings from simplex families.

The current study excluded multiplex ASD families;  however,  in  our  sample  of  simplex  ASD families,  the  brothers  of  children  with  ASD  had significantly higher scores than control boys on the SRS  subscale of Social Motivation.  The  mean difference  in  the  SRS  total  score  between  groups was  6.8  points  with  a  very  large  effect  size,  which suggests a clinically meaningful difference (see Table 1).  In  addition,  contrary  to  the  other  research,  we found  that  SRS  scores  in  the  unaffected  brothers and fathers of children with ASD were not normally distributed;  rather,  they  were  skewed  toward  the pathological  end.  Gender  differences  emerged  in the parents of children with ASD as well as in the siblings  of  children  with  ASD,  with  males  having higher  level  of  QAT  than  females  in  both  groups. These  results  suggest  that  ASD  characteristics  and deficits  in  reciprocal  social  behavior  may  aggregate in  the  unaffected  male  family  members  of  simplex families as well.

Overall, these results support the idea that subclinical traits assessed by the SRS may manifest more frequently or may be more notable among the male  relatives  of  ASD  probands  and  that  elevated scores  aggregate  in  simplex  families.  It  is  possible that  females  have  reduced  susceptibility  to  such ASD  traits as well as reduced penetrance or expression  of  these  traits,  and  they  may  also  be rated differently by their parents as compared with their male counterparts.

Control parents did not differ with regard to their SRS  scores.  Moreover,  contrary  to  the  previous findings  of  Kamio  and  colleagues  (11)  in  their nationwide  study  that  included  more  than  20,000

school-aged children, we found no gender differences  in  the  SRS  scores  of  control  children. This  inconsistent  finding  may  be  the  result  of  the limited  size  and  homogeneity  of  our  sample.  It suggests  that,  among  typically  developing  children, there are no gender differences in social reciprocal behavior development. The SRS scores were normally distributed in the control groups, which is consistent with previous findings that have demonstrated the normal distribution of ASD traits in the general population (6,8).

Lyall and colleagues (15) found evidence of family transmission  of  QAT  in  their  general  population control sample. Among typically developing control children in the present study, child QAT was more strongly  associated  with  mother  QAT  than  father QAT. This finding was particularly  evident  among children with the weakest reciprocal social behavior capacity  (i.e.,  those  children  in  the  highest  SRS quartile;  see  Figure  1).  It  is  possible  that,  among typically developing children, social skills are learned via  interaction  with  the  mother,  regardless  of  the father's reciprocal social behavior capacity. Alternatively, these results may reflect social impairment that is not related to ASD; it has been suggested that low or moderate SRS score elevations may be present with variety of psychiatric disorders (2), and the potential for other psychopathology  to  influence  these  results  cannot be  ruled  out.  For  example,  SRS  scores  that  are elevated in the range of 40 to 55 have been reported among individuals with anxiety disorders and social deficits related to attention-deficit/hyperactivity disorder (32-34).  The  mean  SRS  score  of the control families of our study was less than 40, even for  the  families  of  control  children  in  the  highest quartile  (see  Figure  1).  Thus,  strong  correlations between mothers and children in the control families may be the result of non-ASD psychopathology.  Given  the  small  sample  size  of this study, we cannot rule out chance findings, and these  and  other  explanations  should  be  further explored.

## Limitations

Although the current study had a number  of strengths-including the ability to examine the family transmission of SRS scores, scores in siblings,  and  scores  by  gender  as  well  as  to  have detailed clinical diagnoses confirmed-several limitations should also be noted. First, the definition of a simplex family is subject to bias as a result of undiagnosed parents or siblings or potential changes with  the  addition  of  infant  siblings  who  may  later develop ASD. We selected the families on the basis of  their  present  statuses,  and  we  attempted  to minimize  such  bias  by  inquiring  about  parents'

psychiatric  diagnoses  during  the  ADI-R  interview and  by  asking  parents  about  their  developmental concerns regarding their other children. In addition, diagnostic evaluations were performed on all siblings  for  whom  concerns  were  indicated.  Thus, siblings  in  this  sample  with  high  levels  of  QAT either  did  not  meet  the  diagnostic  criteria  of  ASD despite high levels of quantified ASD traits, or these traits  did  not  cause  clinical  impairment  in  their everyday  lives.  Because  we  had  only  parental  SRS evaluations of the children, reporter bias is possible, as it is with any informant-report measure. However,  Constantino  and  colleagues  (35)  have reported  strong  correlations  between  teacher  and parent reports (r = 0.72), which suggests that such bias is unlikely to drive robust statistical results. We also did not  conduct  full  psychiatric diagnostic evaluations  of  control  families;  thus,  as  previously mentioned,  the  presence  of  non-ASD  diagnoses (e.g.,  major  depressive  disorder,  anxiety  disorders, attention-deficit/hyperactivity  disorder)  cannot  be ruled  out  as  influencing  the  QAT  found  in  our control sample. Finally, we were not able to evaluate how environmental issues, such as caring for a child or  children  with  special  needs,  may  affect  parent and  sibling  features  as  measured  by  the  SRS.  This could be addressed by including control groups of parents  and  siblings  of  children  with  special  needs

other than ASD.

## Conclusions

Clinical Significance

The SRS measures different  domains  of  reciprocal social  capacity  (perception,  cognition,  communication,  and  motivation)  as  well  as  the  presence  of restricted  interests  and  repetitive  behavior.  Results from this study provide important clinical information, particularly with regard to communicating  with  the  parents  and  siblings  of children with ASD. For example, we should consider that the fathers of children with ASD may have difficulty with pragmatic language, joint attention,  communicating  their  feelings  to  others, and  maintaining  conversations.  Although  this  type of prediction is not necessary, it is important for the therapist  to  be  aware  of  any  possible  deficits  and thus  monitor  and  adapt  his  or  her  communication style  accordingly.  Parents-and,  again,  fathers  in particular-may  have  sensory  hyperresponsiveness or hyporesponsiveness that may interfere with their ability  to  concentrate  or  that  may  result  in  tension and discomfort during social situations. The brothers of children  with  ASD  may  be  at  an increased familial risk for exhibiting restricted interests, stereotypic play, routine dependence, resistance to change, and mannerisms  that are qualitatively  similar  to  those  seen  in  children  with ASD.  Moreover,  they  may  avoid  or  dislike  group activities,  and  they  may  hesitate  to  separate  from their parents. This information is extremely clinically  important  when  planning  meetings  with the family and devising family interventions.

Family  members  who  demonstrate  some  ASD symptomatology or subthreshold manifestations of ASD symptoms may require additional  support  to enhance their own reciprocal social abilities to best support  their  children  with  ASD.  Although  the broader autism phenotype is not a diagnostic entity, assessing parent and sibling QAT could be a useful strategy for helping  families  with  children  with ASD,  given  that  even  mildly  manifesting  autistic traits have been found to be associated with internalizing problems, anxiety, mood disorders (3638),  attention-deficit/hyperactivity  disorder  symptoms  (37,39,40),  conduct  problems  (37,41),  and behavioral  problems  (42,43)  as  well  as  problems with  personal  adjustment,  lower  self-esteem,  and less self-reliance (36).

In  addition  to  their  usefulness  for  intervention planning,  the  results  of  this  study  are  clinically significant  as  a  result  of  their  applicability  to  the early  detection  of  new  ASD  cases.  These  results suggest that the infant siblings of children who have been diagnosed with ASD-especially males-may be at risk for developing ASD and should therefore be  carefully  followed  and  screened  during  regular check-ups by trained health care personnel to identify possible delays in reciprocal social behavior capability  and  to  initiate  early  intervention.  These findings  also  support  the  larger  trends  seen  in  the literature,  which  have  demonstrated  the  familiality of broader autism traits.

## References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5). Washington, DC: American Psychiatric Association; 2013.
2. Constantino JN, Gruber CP. Social Responsiveness Scale, Second Edition  (SRS-2).  Torrance,  CA:  Western  Psychological  Services; 2012.
3. Sucksmith E, Roth I, Hoekstra RA. Autistic traits below the clinical threshold: re-examining the broader autism phenotype in the 21 st century. Neuropsychological Rev 2011;21:360-89.
4. Bailey  A,  Palferman  S,  Heavey  L,  LeCouteur  A.  Autism:  The phenotype in relatives. J Autism Dev Disord 1998;28:369-92.
5. Bölte S, Knecht S, Poutska F. A case-control study of personality style  and  psychopathology  in  parents  of  subjects  with  autism.  J Autism Dev Disord 2007;37;243-50.
6. Constantino  JN,  Przybeck  T,  Friesen  D,  Todd  RD.  Reciprocal social behavior in children with and without pervasive developmental disorders. J Dev Behav Pediatr 2000;21:2-11.
7. Constantino JN, Todd RD. Genetic structure of reciprocal social behavior. Am J Psychiatry 2000;157: 2043-5.
8. Constantino JN, Todd RD. Autistic traits in the general population: a twin study. Arch Gen Psychiatry 2003;60:524-30.
9. Constantino  JN,  Todd  RD.  Intergenerational  transmission of subthreshold autistic traits in the general population. Biol Psychiatry 2005;57:655-60.
10. Constantino  JN,  Lajonchere  C,  Lutz  M,  et  al.  Autistic  social impairment in the siblings of children with pervasive developmental disorders. Am J Psychiatry 2006;163:249-96.
11. Kamio Y, Inada N, Moriwaki A, et al. Quantitative  autistic  traits ascertained in a national survey of 22 529 Japanese schoolchildren. Acta Psychiatr Scand 2012;128:45-53.
12. Murphy M, Bolton PF, Pickels A, Fombonne E, Piven J, Rutter M. Personality  traits  of  the  relatives  of  autistic  probands.  Psychol Medicine 2000;30:1411-24.
13. Virkud YV, Todd RD, Abbacchi AM, Zhang Y, Constantino JN. Familial  aggregation  of  quantitative  autistic  traits  in  multiplex versus simplex autism. Am J Med Genet Part B 2009;150B:328-34.
14. Schwichtenberg AJ, Young GS, Sigman M, Hutman T, Ozonoff S. Can family affectedness inform infant sibling outcomes of autism spectrum disorders? J Child Psychol Psychiatry 2010;51:1021-30.
15. Lyall  K,  Constantino  J,  Weisskopf  M,  Roberts  A,  Ascherio  A, Santangelo  S.  Parental  social  responsiveness  and  risk  of  autism spectrum disorder  in  offspring.  JAMA  Psychiatry  2014;71(8):93642.
16. Piven  J.  The  broad  autism  phenotype:  a  complementary  strategy for  molecular  genetic  studies  of  autism.  Am  J  Med  Genet  B (Neuropsychiatric Genetics) 2001;105:34-5.
17. Miles JH, Takahashi TN, Bagby S, et al. Essential versus complex autism: definition of fundamental prognostic subtypes. Am J Med Genet A 2005;135(2):171-80.
18. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. Am  J Psychiatry 2010;167(11):1349-56.
19. Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins the  Autism  Consortium.  A  genome-wide  linkage  and  association scan reveals novel loci for autism. Nature 2009;461(17265):802-8.
20. Ehlers S, Gillberg C. The epidemiology of Asperger syndrome. a total population study. J Child Psychol Psychiatry 1993;34:1327-50.
21. Ehlers  S,  Gillberg  C,  Wing  L.  A  screening  questionnaire  for Asperger  syndrome  and  other  high-functioning  autism  spectrum disorders in school age children. J Autism Dev Disord 1999;29:129-41.
22. World Health Organization. International Classification of Mental and Behavioural Disorders. ICD-10. Geneva: World Health Organization; 1993.
23. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4 th  ed) (DSM-IV). Washington, DC: American Psychiatric Association; 1994.
24. Mattila MLM, Jussila K, Linna SL, et al. Validation of the Finnish Autism  Spectrum  Screening  Questionnaire  (ASSQ)  for  clinical settings  and  total  population  screening.  J  Autism  Dev  Disord 2012;42:2162-80.
25. Lord  C,  Rutter  M,  LeCouteur  A.  Autism  Diagnostic  InterviewRevised (3 rd  ed). Los Angeles, CA: Western Psychological Services; 1995.
26. Lord  C,  Rutter  M,  DiLavore  PC,  Risi  S.  Autism  Diagnostic Observation  Schedule.  Los  Angeles,  CA:  Western  Psychological Services; 2000.

27. Constantino  JN,  Gruber  CP.  The  Social  Responsiveness  Scale Manual. California: Western Psychological services, 2005.
28. Constantino  JN,  Davis  SA,  Todd  RD,  et  al.Validation  of  a  brief quantitative  measure  of  autistic  traits:  comparison  of  the  social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord 2003;33(4):427-33.
29. Jussila  K,  Kuusikko-Gauffin  S,  Mattila  ML,  et  al.  Cross-Cultural differences in  the  Parent  Rated  Social  Responsiveness  Scale? Evaluation of the Finnish version among high-functioning school aged males with and without autism spectrum disorder. Res Autism Spectr Disord 2015;9:38-44.
30. Robinson E, Lichtenstein P, Anckarsater H, Happe F, Ronald A. Examining  and  interpreting  the  female  protective  effect  against autistic behaviour. Proc Natl Acad Sci USA 2013;110(13):5258-62.
31. Constantino J, Charman T. Gender bias, female resilience, and the sex ratio in autism. J Am  Acad  Child Adolesc Psychiatry 2012;51(8):756-8.
32. Connor  M,  Puleo  P,  Kendell  P.  Anxiety  disorders  in  typically developing  youth:  autism  spectrum  symptoms  as  a  predictor  of cognitive-behavioral treatment. J Autism Dev Dis 2010;41(3):27586.
33. Towbin K, Pradella A, Gorrindo T, Pine D, Leibenluft E. Autism spectrum  traits  in  children  with  mood  and  anxiety  disorders.  J Child Adolesc Psychopharmacol 2005;15(3):452-64.
34. Reiersen  A,  Constantino  J,  Volk  H,  Todd  R.  Autistic  traits  in  a population-based ADHD twin sample. J Child Psychol Psychiatry 2007;48(5):464-72.
35. Constantino JN, Lavesser PD, Zhang Y, Abbacchi AM, Gray T, Todd RD. Rapid quantitative assessment of autistic social impairment  by  classroom  teachers.  J  Am  Acad  Child  Adolesc Psychiatry 2007;46(12):1668-76.
36. Kanne S, Christ S, Reiersen A. Psychiatric symptoms and psychosocial  difficulties  in young  adults  with  autistic  traits. J Autism Dev Disord 2009;39:827-33.
37. Lundström  S,  Chang  Z,  Kerekes  N,  et  al.  Autistic-like  traits  and their  association  with  mental  health  problems  in  two  nationwide twin cohorts of children and adults. Psychol Med 2011;41:2423-33.
38. Pine  DS,  Guyer  AE,  Goldwin  M,  Towbin  KA,  Leibenluft  E. Autism  spectrum  disorders  scale  scores  in  pediatric  mood  and anxiety disorders. J Am Acad Child Adolesc Psychiatry 2008;47;652-61.
39. Reiersen  AM,  Constantino  JN,  Grimmer  M,  Martin  NG,  Todd RD.  Evidence  for  shared  genetic influences on  self-reported ADHD and  autistic  symptoms  in  young  adult  Australian  twins. Twin Res Hum Genet 2008;11:579-85.
40. Rommelse NN, Altink ME, Fliers EA, et al. Comorbid problems in ADHD:  degree of association, shared endophenotypes, and formation of distinct subtypes. J Abnorm Child Psychol 2009;37(6):793-804.
41. Gilmour  J,  Hill  B,  Place  M,  Skuse  DH.  Social  communication deficits  in  conduct  disorder:  a  clinical  and  community  survey.  J Child Psychol Psychiatry2004;45:967-78.
42. Hoekstra  RA,  Bartels M,  Hudziak  JJ, Van  Beijsterveldt  TC, Boomsma  DI.  Genetic  and  environmental  covariation  between autistic  traits  and  behavioural  problems.  Twin  Res  Hum  Genet 2007;10:853-60.
43. Hus  V,  Bishop  S,  Gotham  K,  Huerta  M,  Lord  C.  Factors influencing  scores  on  the  social  responsiveness  scale.  J  Child Psychol Psychiatry 2013;54:216-24.

## Acknowledgements

We  thank  the  participants  and  their  parents,  who graciously  gave  their  time  to  participate  in  this study.  This  study  received  financial  support  from the  Alma  and  K.  A.  Snellman  Foundation,  Oulu, Finland;  the  Emil  Aaltonen  Foundation,  Finland; Northern Ostrobothnia Hospital District; the Sigrid Jusélius  Foundation,  Finland;  the  Thule  Institute, University  of  Oulu,  Finland;  the  Child  Psychiatric Research Foundation, Finland. The Graduate School of Circumpolar Wellbeing, Health and Adaptation  is  acknowledged  for  its  support.  We would  also  like  to  thank  the  National  Alliance  for Autism  Research  for  financial  support  granted  to David Pauls. For data collection  we wish  to  thank Child Psychiatrist, PhD Sirkka-Liisa Linna and PhD Marko Kielinen.