Adjusting head circumference for covariates in autism: Clinical correlates of a highly heritable continuous trait

Pauline Chaste; Lambertus Klei; Stephan J. Sanders; Michael T. Murtha; Vanessa Hus; Jennifer K. Lowe; A. Jeremy Willsey; Daniel Moreno-De-Luca; Timothy W. Yu; Eric Fombonne; Daniel Geschwind; Dorothy E. Grice; David H. Ledbetter; Catherine Lord; Shrikant M. Mane; Christa Lese Martin; Donna M. Martin; Eric M. Morrow; Christopher A. Walsh; James S. Sutcliffe; Matthew W. State; Bernie Devlin; Edwin H. Cook; Soo Jeong Kim

doi:10.1016/j.biopsych.2013.04.018

Adjusting head circumference for covariates in autism: Clinical correlates of a highly heritable continuous trait

Pauline Chaste, Lambertus Klei, Stephan J. Sanders, Michael T. Murtha, Vanessa Hus, Jennifer K. Lowe, A. Jeremy Willsey, Daniel Moreno-De-Luca, Timothy W. Yu, Eric Fombonne, Daniel Geschwind, Dorothy E. Grice, David H. Ledbetter, Catherine Lord, Shrikant M. Mane, Christa Lese Martin, Donna M. Martin, Eric M. Morrow, Christopher A. Walsh, James S. SutcliffeMatthew W. State, Bernie Devlin, Edwin H. Cook, Soo Jeong Kim

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Original language	English (US)
Pages (from-to)	576-584
Number of pages	9
Journal	Biological Psychiatry
Volume	74
Issue number	8
DOIs	https://doi.org/10.1016/j.biopsych.2013.04.018
State	Published - Oct 15 2013
Externally published	Yes

Keywords

ASD
IQ
autism spectrum disorder
body metrics
genetic ancestry
head circumference

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2013.04.018

Cite this

Chaste, P., Klei, L., Sanders, S. J., Murtha, M. T., Hus, V., Lowe, J. K., Willsey, A. J., Moreno-De-Luca, D., Yu, T. W., Fombonne, E., Geschwind, D., Grice, D. E., Ledbetter, D. H., Lord, C., Mane, S. M., Lese Martin, C., Martin, D. M., Morrow, E. M., Walsh, C. A., ... Kim, S. J. (2013). Adjusting head circumference for covariates in autism: Clinical correlates of a highly heritable continuous trait. Biological Psychiatry, 74(8), 576-584. https://doi.org/10.1016/j.biopsych.2013.04.018

Chaste, P, Klei, L, Sanders, SJ, Murtha, MT, Hus, V, Lowe, JK, Willsey, AJ, Moreno-De-Luca, D, Yu, TW, Fombonne, E, Geschwind, D, Grice, DE, Ledbetter, DH, Lord, C, Mane, SM, Lese Martin, C, Martin, DM, Morrow, EM, Walsh, CA, Sutcliffe, JS, State, MW, Devlin, B, Cook, EH & Kim, SJ 2013, 'Adjusting head circumference for covariates in autism: Clinical correlates of a highly heritable continuous trait', Biological Psychiatry, vol. 74, no. 8, pp. 576-584. https://doi.org/10.1016/j.biopsych.2013.04.018

@article{09405edb159b4f77ab56059d5c61352d,

title = "Adjusting head circumference for covariates in autism: Clinical correlates of a highly heritable continuous trait",

abstract = "Background 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. Methods 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. Results 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. Conclusions 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.",

keywords = "ASD, IQ, autism spectrum disorder, body metrics, genetic ancestry, head circumference",

author = "Pauline Chaste and Lambertus Klei and Sanders, {Stephan J.} and Murtha, {Michael T.} and Vanessa Hus and Lowe, {Jennifer K.} and Willsey, {A. Jeremy} and Daniel Moreno-De-Luca and Yu, {Timothy W.} and Eric Fombonne and Daniel Geschwind and Grice, {Dorothy E.} and Ledbetter, {David H.} and Catherine Lord and Mane, {Shrikant M.} and {Lese Martin}, Christa and Martin, {Donna M.} and Morrow, {Eric M.} and Walsh, {Christopher A.} and Sutcliffe, {James S.} and State, {Matthew W.} and Bernie Devlin and Cook, {Edwin H.} and Kim, {Soo Jeong}",

note = "Funding Information: We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on the Simons Foundation Autism Research Initiative (SFARI) Base. Approved researchers can obtain the SSC population data set described in this study ( http://sfari.org/resources/sfari-base ) by applying at https://base.sfari.org . This work was supported by a grant from the Simons Foundation (Grant No. SFARI 124827 to the investigators of the SSC Genetic Consortium), National Institutes of Health (NIH; Grant No. K23MH082883 (SJK), NIH R01HD065272 (CL), NIH R01MH089390 (CL), and Fondamental Foundation (PC). ",

year = "2013",

month = oct,

day = "15",

doi = "10.1016/j.biopsych.2013.04.018",

language = "English (US)",

volume = "74",

pages = "576--584",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "8",

}

TY - JOUR

T1 - Adjusting head circumference for covariates in autism

T2 - Clinical correlates of a highly heritable continuous trait

AU - Chaste, Pauline

AU - Klei, Lambertus

AU - Sanders, Stephan J.

AU - Murtha, Michael T.

AU - Hus, Vanessa

AU - Lowe, Jennifer K.

AU - Willsey, A. Jeremy

AU - Moreno-De-Luca, Daniel

AU - Yu, Timothy W.

AU - Fombonne, Eric

AU - Geschwind, Daniel

AU - Grice, Dorothy E.

AU - Ledbetter, David H.

AU - Lord, Catherine

AU - Mane, Shrikant M.

AU - Lese Martin, Christa

AU - Martin, Donna M.

AU - Morrow, Eric M.

AU - Walsh, Christopher A.

AU - Sutcliffe, James S.

AU - State, Matthew W.

AU - Devlin, Bernie

AU - Cook, Edwin H.

AU - Kim, Soo Jeong

N1 - Funding Information: We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on the Simons Foundation Autism Research Initiative (SFARI) Base. Approved researchers can obtain the SSC population data set described in this study ( http://sfari.org/resources/sfari-base ) by applying at https://base.sfari.org . This work was supported by a grant from the Simons Foundation (Grant No. SFARI 124827 to the investigators of the SSC Genetic Consortium), National Institutes of Health (NIH; Grant No. K23MH082883 (SJK), NIH R01HD065272 (CL), NIH R01MH089390 (CL), and Fondamental Foundation (PC).

PY - 2013/10/15

Y1 - 2013/10/15

N2 - Background 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. Methods 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. Results 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. Conclusions 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.

AB - Background 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. Methods 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. Results 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. Conclusions 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.

KW - ASD

KW - IQ

KW - autism spectrum disorder

KW - body metrics

KW - genetic ancestry

KW - head circumference

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U2 - 10.1016/j.biopsych.2013.04.018

DO - 10.1016/j.biopsych.2013.04.018

M3 - Article

C2 - 23746936

AN - SCOPUS:84884674769

SN - 0006-3223

VL - 74

SP - 576

EP - 584

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 8

ER -

Adjusting head circumference for covariates in autism: Clinical correlates of a highly heritable continuous trait

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Keywords

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