Molecular Psychiatry (2000) 5, 363–368  2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00 www.nature.com/mp IMMEDIATE COMMUNICATION Apolipoprotein E is a genetic risk factor for fetal iodine deficiency disorder in China HY Wang 1 , FC Zhang 2 , JJ Gao 2 , JB Fan 1 , P Liu 3 , ZJ Zheng 2 , H Xi 2 , Y Sun 2 , XC Gao 2 , TZ Huang 4 , ZJ Ke 4 , GR Guo 4 , GY Feng 5 , G Breen 6 , D St Clair 6 and L He 1,3,7 1 Shanghai Institute of Physiology, Chinese Academy Sciences, Shanghai 200031, People’s Republic of China; 2 Institute of Mental Retardation, Northwestern University, Xian 710062, People’s Republic of China; 3 Shanghai Research Center of Life Sciences, Shanghai 200031, People’s Republic of China; 4 Yunyang Medical College, Hubei.Shiyan 442000, People’s Republic of China; 5 Shanghai Mental Health Center, Shanghai 200030, People’s Republic of China; 6 Department of Mental Health, University of Aberdeen, Medical School, Foresterhill, Aberdeen AB25 2ZD, Scotland; 7 College of Life Science and Biotechnology, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai 200030, People’s Republic of China Fetal iodine deficiency disorder (FIDD) is the principal form of endemic cretinism, and the most common cause of preventable mental deficiency in the world. However not everyone at risk develops FIDD and familial aggregation is common. This suggests that genetic factors may also be involved. The Apolipoprotein E (APOE) gene encodes for a lipoprotein that pos- sesses a thyroid hormone binding domain, and APOE genotype may affect the efficiency with which thyroid hormone influences neuronal cell growth during the first and second trimesters of fetal development. We have compared ApoE genotypes in 91 FIDD cases with 154 local control subjects, recruited from three iodine deficiency areas in central China. We have also genotyped 42 FIDD family cases and 158 normal individuals from the families of local controls, and 375 population controls from Shanghai. APOE 4 genotypes were significantly enriched in FIDD probands from each of the three iodine deficiency areas; the 4 allele frequency was 16% vs 6% in controls. The same effect was also observed when we compared FIDD family cases with controls and control families. Our data suggest that in iodine-deficient areas, the APOE 4 allele is a genetic risk factor for FIDD. The phenomenon may affect population selec- tion and contribute to the low frequency of the 4 allele in Chinese compared to Caucasian populations. Molecular Psychiatry (2000) 5, 363–368. Keywords: fetal iodine deficiency disorder; endemic cretinism; APOE genotype; apolipoprotein; China; mental retardation Introduction Iodine deficiency is the commonest cause of prevent- able mental retardation. 1 One hundred thousand chil- dren a year are born with features of frank cretinism, 2 and many times more are born with lesser mental and neurological deficits attributable to iodine deficiency. 3 The neurological form of cretinism, also known as fetal iodine deficiency disorder (FIDD), predominates in China and is characterized by mental retardation and abnormalities of speech, hearing impairment, and dis- turbance of posture and gait. 3 It results from inadequate amounts of thyroid hormone being available to the developing fetal brain in the second and probably some of the first trimester. 4,5 The damage is permanent and cannot be reversed by postnatal thyroid hormone supplementation. This contrasts with the myxedemat- Correspondence: L He, Shanghai Institute of Physiology, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, People’s Republic of China. E-mail: helinannahotmail.com Received 3 December 1999; revised and accepted 28 January 2000 ous forms of cretinism whose severity depends upon the duration and magnitude of postnatal hypothyroid- ism, and is treatable to a large extent by postnatal thy- roid hormone therapy. 6 Clinicopathological studies of FIDD are limited in number. Macroscopically the brain may be smaller than normal but is otherwise unremarkable. 7 Micro- scopic examination shows reduced numbers, irregular arrangement and degeneration of neurons in several areas of the brain. The neurons have fewer dendrite branches, and the number and pattern of their spines is deranged. 8 While fetal iodine deficiency during early development is the major agent responsible for neuro- logical cretinism/FIDD, it does not explain why only some of those at risk develop FIDD. Familial clustering is reported, which suggests that genetic factors may interact with an iodine-deficient physical environment to determine overall risk of FIDD. 2 APOE is the struc- tural gene for apolipoprotein E (apoE), an apolipopro- tein involved in lipid transport and metabolism. It is synthesized in the liver and by the astrocyte cells of the CNS. The three major isoforms (E2, E3, E4), are