Adjusting Head Circumference for Covariates in Autism: Clinical Correlates of a Highly Heritable Continuous Trait


      Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort.


      We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters.


      Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC.


      Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • American Psychiatric Association (2000)
        Diagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR).
        4th ed. American Psychiatric Publishing, Washington, DC2000
        • Courchesne E.
        • Carper R.
        • Akshoomoff N.
        Evidence of brain overgrowth in the first year of life in autism.
        JAMA. 2003; 290: 337-344
        • Aylward E.H.
        • Minshew N.J.
        • Field K.
        • Sparks B.F.
        • Singh N.
        Effects of age on brain volume and head circumference in autism.
        Neurology. 2002; 59: 175-183
        • Hazlett H.C.
        • Poe M.
        • Gerig G.
        • Smith R.G.
        • Provenzale J.
        • Ross A.
        • et al.
        Magnetic resonance imaging and head circumference study of brain size in autism: Birth through age 2 years.
        Arch Gen Psychiatry. 2005; 62: 1366-1376
        • Webb S.J.
        • Nalty T.
        • Munson J.
        • Brock C.
        • Abbott R.
        • Dawson G.
        Rate of head circumference growth as a function of autism diagnosis and history of autistic regression.
        J Child Neurol. 2007; 22: 1182-1190
        • Bailey A.
        • Le Couteur A.
        • Gottesman I.
        • Bolton P.
        • Simonoff E.
        • Yuzda E.
        • et al.
        Autism as a strongly genetic disorder: Evidence from a British twin study.
        Psychol Med. 1995; 25: 63-77
        • Bolton P.
        • Macdonald H.
        • Pickles A.
        • Rios P.
        • Goode S.
        • Crowson M.
        • et al.
        A case–control family history study of autism.
        J Child Psychol Psychiatry. 1994; 35: 877-900
        • Davidovitch M.
        • Patterson B.
        • Gartside P.
        Head circumference measurements in children with autism.
        J Child Neurol. 1996; 11: 389-393
        • Lainhart J.E.
        • Piven J.
        • Wzorek M.
        • Landa R.
        • Santangelo S.L.
        • Coon H.
        • et al.
        Macrocephaly in children and adults with autism.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 282-290
        • Stevenson R.E.
        • Schroer R.J.
        • Skinner C.
        • Fender D.
        • Simensen R.J.
        Autism and macrocephaly.
        Lancet. 1997; 349: 1744-1745
        • Fombonne E.
        • Roge B.
        • Claverie J.
        • Courty S.
        • Fremolle J.
        Microcephaly and macrocephaly in autism.
        J Autism Dev Disord. 1999; 29: 113-119
        • Miles J.H.
        • Hadden L.L.
        • Takahashi T.N.
        • Hillman R.E.
        Head circumference is an independent clinical finding associated with autism.
        Am J Med Genet. 2000; 95: 339-350
        • Deutsch C.K.
        • Joseph R.M.
        Brief report: cognitive correlates of enlarged head circumference in children with autism.
        J Autism Dev Disord. 2003; 33: 209-215
        • Dementieva Y.A.
        • Vance D.D.
        • Donnelly S.L.
        • Elston L.A.
        • Wolpert C.M.
        • Ravan S.A.
        • et al.
        Accelerated head growth in early development of individuals with autism.
        Pediatr Neurol. 2005; 32: 102-108
        • van Daalen E.
        • Swinkels S.H.
        • Dietz C.
        • van Engeland H.
        • Buitelaar J.K.
        Body length and head growth in the first year of life in autism.
        Pediatr Neurol. 2007; 37: 324-330
        • Ververi A.
        • Vargiami E.
        • Papadopoulou V.
        • Tryfonas D.
        • Zafeiriou D.I.
        Clinical and laboratory data in a sample of Greek children with autism spectrum disorders.
        J Autism Dev Disord. 2012; 42: 1470-1476
        • Davidovitch M.
        • Golan D.
        • Vardi O.
        • Lev D.
        • Lerman-Sagie T.
        Israeli children with autism spectrum disorder are not macrocephalic.
        J Child Neurol. 2011; 26: 580-585
        • Mraz K.D.
        • Green J.
        • Dumont-Mathieu T.
        • Makin S.
        • Fein D.
        Correlates of head circumference growth in infants later diagnosed with autism spectrum disorders.
        J Child Neurol. 2007; 22: 700-713
        • Barnard-Brak L.
        • Sulak T.
        • Hatz J.K.
        Macrocephaly in children with autism spectrum disorders.
        Pediatr Neurol. 2011; 44: 97-100
        • Bushby K.M.
        • Cole T.
        • Matthews J.N.
        • Goodship J.A.
        Centiles for adult head circumference.
        Arch Dis Child. 1992; 67: 1286-1287
        • Martins A.M.
        • Lyons Jones K.
        Correlation of occipitofrontal circumference and crown-rump length from birth to 15 months.
        Clin Dysmorphol. 1994; 3: 157-159
        • Sacco R.
        • Militerni R.
        • Frolli A.
        • Bravaccio C.
        • Gritti A.
        • Elia M.
        • et al.
        Clinical, morphological, and biochemical correlates of head circumference in autism.
        Biol Psychiatry. 2007; 62: 1038-1047
        • Chawarska K.
        • Campbell D.
        • Chen L.
        • Shic F.
        • Klin A.
        • Chang J.
        Early generalized overgrowth in boys with autism.
        Arch Gen Psychiatry. 2011; 68: 1021-1031
        • Lainhart J.E.
        • Bigler E.D.
        • Bocian M.
        • Coon H.
        • Dinh E.
        • Dawson G.
        • et al.
        Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism.
        Am J Med Genet A. 2006; 140: 2257-2274
        • Rommelse N.N.
        • Peters C.T.
        • Oosterling I.J.
        • Visser J.C.
        • Bons D.
        • van Steijn D.J.
        • et al.
        A pilot study of abnormal growth in autism spectrum disorders and other childhood psychiatric disorders.
        J Autism Dev Disord. 2011; 41: 44-54
        • Nordahl C.W.
        • Lange N.
        • Li D.D.
        • Barnett L.A.
        • Lee A.
        • Buonocore M.H.
        • et al.
        Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders.
        Proc Natl Acad Sci U S A. 108. 2011: 20195-20200
        • Rutter M.
        • Le Couteur A.
        • Lord C.
        Autism Diagnostic Interview—Revised WPS Edition Manual.
        Western Psychological Services, Los Angeles, CA2008
        • Lord C.
        • Rutter M.
        • DiLavore P.C.
        • Risi S.
        Autism Diagnostic Observation Schedule WPS Edition Manual. Western Psychological Services, Los Angeles2006
        • Sparrow S.S.
        • Cicchetti D.V.
        • Bella D.A.
        Vineland Adaptive Behavior Scales—2nd edition manual.
        NCS Pearson, Minneapolis2005
        • Elliott C.D.
        Differential Ability Scale.
        2nd ed. Psychological Corporation, San Antonio, TX2007
        • Wechsler D.
        The Wechsler Intelligence Scale for Children—4th ed.
        Pearson Assessment, London2004
        • Mullen E.M.
        The Mullen Scales of Early Learning.
        American Guidance Service, Circle Pines, MN1995
        • Raven J.
        Manual for Raven’s Progressive Matrices and Vocabulary Scales. Research Supplement No. 1: The 1979 British Standardisation of the Standard Progressive Matrices and Mill Hill Vocabulary Scales, Together With Comparative Data From Earlier Studies in the UK, US, Canada, Germany and Ireland.
        Harcourt Assessment, San Antonio, TX1981
        • Dunn L.M.
        • Dunn D.M.
        Peabody Picture Vocabulary Test, 4th ed. (PPVT-IV): A Measure of Receptive Vocabulary for Standard American English.
        San Antonio, TX: Pearson, 2007
      1. Klei L, Kent BP, Melhem N, Devlin B, Roeder K (2011): GemTools: A fast and efficient approach to estimating genetic ancestry. Available at:

        • Perez-Enciso M.
        • Misztal I.
        Qxpak.5: Old mixed model solutions for new genomics problems.
        BMC Bioinformatics. 2011; 12: 202
        • Perez-Enciso M.
        • Misztal I.
        Qxpak: A versatile mixed model application for genetical genomics and QTL analyses.
        Bioinformatics. 2004; 20: 2792-2798
        • Roche A.F.
        • Mukherjee D.
        • Guo S.M.
        • Moore W.M.
        Head circumference reference data: birth to 18 years.
        Pediatrics. 1987; 79: 706-712
        • Gotham K.
        • Pickles A.
        • Lord C.
        Standardizing ADOS scores for a measure of severity in autism spectrum disorders.
        J Autism Dev Disord. 2009; 39: 693-705
        • Courchesne E.
        • Karns C.M.
        • Davis H.R.
        • Ziccardi R.
        • Carper R.A.
        • Tigue Z.D.
        • et al.
        Unusual brain growth patterns in early life in patients with autistic disorder: An MRI study.
        Neurology. 2001; 57: 245-254
        • Piven J.
        • Arndt S.
        • Bailey J.
        • Andreasen N.
        Regional brain enlargement in autism: A magnetic resonance imaging study.
        J Am Acad Child Adolesc Psychiatry. 1996; 35: 530-536
        • Piven J.
        • Nehme E.
        • Simon J.
        • Barta P.
        • Pearlson G.
        • Folstein S.E.
        Magnetic resonance imaging in autism: Measurement of the cerebellum, pons, and fourth ventricle.
        Biol Psychiatry. 1992; 31: 491-504
        • Sparks B.F.
        • Friedman S.D.
        • Shaw D.W.
        • Aylward E.H.
        • Echelard D.
        • Artru A.A.
        • et al.
        Brain structural abnormalities in young children with autism spectrum disorder.
        Neurology. 59. :, 2002: 184-192
        • Lindley A.A.
        • Benson J.E.
        • Grimes C.
        • Cole 3rd, T.M.
        • Herman A.A.
        The relationship in neonates between clinically measured head circumference and brain volume estimated from head CT-scans.
        Early Hum Dev. 1999; 56: 17-29
        • Bartholomeusz H.H.
        • Courchesne E.
        • Karns C.M.
        Relationship between head circumference and brain volume in healthy normal toddlers, children, and adults.
        Neuropediatrics. 2002; 33: 239-241
        • Weaver D.D.
        • Christian J.C.
        Familial variation of head size and adjustment for parental head circumference.
        J Pediatr. 1980; 96: 990-994
        • Smit D.J.
        • Luciano M.
        • Bartels M.
        • van Beijsterveldt C.E.
        • Wright M.J.
        • Hansell N.K.
        • et al.
        Heritability of head size in Dutch and Australian twin families at ages 0–50 years.
        Twin Res Hum Genet. 2010; 13: 370-380
        • Klei L.
        • Sanders S.J.
        • Murtha M.T.
        • Hus V.
        • Lowe J.K.
        • Willsey A.J.
        • et al.
        Common genetic variants, acting additively, are a major source of risk for autism.
        Mol Autism. 2012; 3: 9
        • Roche A.F.
        Secular trends in human growth, maturation, and development.
        Monogr Soc Res Child Dev. 1979; 44: 1-120
        • Hamill P.V.
        • Drizd T.A.
        • Johnson C.L.
        • Reed R.B.
        • Roche A.F.
        NCHS growth curves for children birth–18 years. United States. Vital Health Stat 11. 1977; (1–74): (165):i-iv
        • Kuczmarski R.J.
        • Ogden C.L.
        • Guo S.S.
        • Grummer-Strawn L.M.
        • Flegal K.M.
        • Mei Z.
        • et al.
        2000 CDC growth charts for the United States: Methods and development.
        Vital Health Stat. 2002; 11: 1-190
        • McDowell M.A.
        • Fryar C.D.
        • Ogden C.L.
        • Flegal K.M.
        Anthropometric reference data for children and adults: United States, 2003–2006. 2008 (National Health Statistics Reports, No. 10. Available at: Accessed October 22, 2008)
        • Ounsted M.
        • Moar V.A.
        • Scott A.
        Head circumference charts updated.
        Arch Dis Child. 1985; 60: 936-939
        • Miller A.K.
        • Corsellis J.A.
        Evidence for a secular increase in human brain weight during the past century.
        Ann Hum Biol. 1977; 4: 253-257
        • Moon J.S.
        Secular trends of body sizes in Korean children and adolescents: From 1965 to 2010.
        Korean J Pediatr. 2011; 54: 436-442
        • Wikland K.A.
        • Luo Z.C.
        • Niklasson A.
        • Karlberg J.
        Swedish population-based longitudinal reference values from birth to 18 years of age for height, weight and head circumference.
        Acta Paediatr. 2002; 91: 739-754
      2. Fryar CD, Gu Q, Ogden CL (2012): Anthropometric reference data for children and adults: United States, 2007–2010. Vital Health Stat 11 (252). Available at: Accessed October, 2012.

        • O’Roak B.J.
        • Vives L.
        • Fu W.
        • Egertson J.D.
        • Stanaway I.B.
        • Phelps I.G.
        • et al.
        Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.
        Science. 2012; 338: 1619-1622